Specific eatable taste modifiers

ABSTRACT

Ingestible compounds which are substantially tasteless and which have been found to be effective reducers or eliminators of undesirable tastes for eatables.

This application is a divisional of application Ser. No. 08/451,063filed May 25, 1995 now allowed; which in turn is a continuation ofapplication Ser. No. 08/067,537 filed on May 26, 1993 now abandoned;which in turn is a continuation-in-part of application serial no.PCT/US92/10179 filed on Nov. 24, 1992 which designates the United Statesand a continuation-in-part of application Ser. No. 07/799,207 filed Nov.27, 1991 now abandoned, which in turn is a continuation-in-part ofapplication Ser. No. 07/531,388 filed Jun. 1, 1990, now U.S. Pat. No.5,232,735.

BACKGROUND OF THE INVENTION

This invention relates in general to taste modifying compounds. Moreparticularly it relates to tastands, as such term is used hereinbelow,to reduce or eliminate undesirable tastes, as such term is usedhereinbelow.

There are numerous compounds that are known to be salty but haveproblems associated with their use as salt substitutes. Potassiumchloride has a pronounced strong bitter undesirable taste, as such termis used hereinbelow, and ammonium chloride has, at least as sensed insome people, a fishy taste associated with it. Lithium chloride,although a somewhat better tasting salt, is highly toxic. To date thereis no universally satisfactory salty tasting substitute for the sodiumion.

The desirability of reducing the sodium ion intake of humans is welldocumented. An excessive intake of sodium ion has been linked to highblood pressure and premature heart attack. This problem has beenaddressed by numerous researchers in a variety of ways over the past twodecades.

At the current time, reduction of sodium ion intake is achieved via acombination of abstinence and/or the substitution of potassium chloridefor sodium chloride and/or mixing sodium chloride with fillers so thatless sodium chloride is used on the eatable, as defined hereinbelow,although the volume of material added to the eatable is the same. Inaddition, for materials that are coated with a surface salt such as forexample potato chips, it is known that smaller particle size for thesodium chloride results in a saltier taste perception, and thereforeless salt need be added to obtain an equal level of salt perception.

There are a variety of products on the market today utilizing potassiumchloride as a saltening agent. All of these salt substitutes rely onother ingredients which are mixed with the potassium chloride to maskthe bitter undesirable taste, as such term is used hereinbelow, ofpotassium chloride. These highly flavorful ingredients consist of itemssuch as onion, garlic, paprika, red pepper, chili powder and many otherspices. None of these mixtures or potassium chloride itself has foundwide-spread acceptance, probably because the bitter taste of potassiumion is still detectable.

In addition to reducing sodium ion intake by the substitution of sodiumchloride by potassium chloride, there are numerous other examples ofcompounds containing sodium ions used in the food industry which couldbenefit by the substitution of potassium ion for sodium ion if thebitter taste associated with potassium ion were eliminated. For example,sodium baking soda or baking powder could be substituted with potassiumbaking soda and potassium baking powder, respectively, in productsrequiring leavening agents. A few more examples of substitutions whichcould be made are:

A. monopotassium glutamate for monosodium glutamate in the case offlavoring, and,

B. potassium nitrate or nitrite for the corresponding sodium nitrate ornitrite in the case of preservatives, and,

C. potassium benzoate, potassium sulfate or sulfite in place ofcorresponding sodium salts in the case of preservatives would also behighly desirable.

In addition, numerous eatables, as defined hereinbelow, on the markettoday have a naturally bitter taste and/or undesirable taste, as suchterms are used hereinbelow. Many of these materials, as currently used,have the bitter taste or aftertaste partially masked by additives, suchas flavorings similar to those stated above. Many of these materials arestill bitter and/or still have an aftertaste and could benefit by havinga tastand, as such term is used hereinbelow, mixed or ingested alongwith them to eliminate or substantially reduce the undesirable taste(s),as such term is used hereinbelow. Such eatables as for example,pharmaceuticals, antibiotics, pain killers, aspirin, codeine, ibuprofen,acetaminophen, caffeine, and unsweetened chocolate, and sweeteners, assuch term is used hereinbelow, can have their undesirable tastes, assuch term is used hereinbelow, reduced and/or eliminated as well ashaving their palatability enhanced by the use of a tastand, as such termis used hereinbelow. In general, any eatable which has a naturallyundesirable taste, as such term is used hereinbelow, should be able tobe rendered more palatable by the addition of an appropriate tastand, assuch term is used hereinbelow.

SUMMARY OF THE INVENTION

Differences in taste perception between individuals seem to be common.There are more than just the basic or "true" tastes of sweet, sour,bitter, umami, and salty. A few examples of these other tastes arealkaline, astringent, tangy, dry, sharp, cool, hot, burning, acidic,spicy, pungent, and/or metallic.

As used herein and in the appended claims, "undesirable taste(s)" shallmean any taste which is sweet, bitter, sour, alkaline, astringent,tangy, dry, sharp, cool, hot, burning, acidic, spicy, pungent, woody,smokey, umami and/or metallic. Such undesirable taste shall include anyand all tastes, if such taste(s) is unwanted and include any and allaftertaste(s), if such aftertaste is unwanted.

There can be more than one perception of a single taste, whether suchtaste is a "true" taste or another taste. There are a number ofdifferent "bitter" tastes that can be noted by some individuals. Thiscan be demonstrated by the following:

Some tastands which reduce or substantially eliminate the off-taste of:

1. For example, caffeine, may have little or no effect on apharmaceutical and/or the off-taste of KCl, or,

2. For example, L-aspartyl-L-phenylalanine methyl ester (Aspartame) mayhave little or no effect on the off-taste of another high intensitysweetener such as saccharin.

Some specific examples of these effects are:

A. L-Aspartyl-L-phenylalanine will have a substantial effect on theoff-taste associated with L-aspartyl-L-phenylalanine methyl ester(Aspartame®), while it has less effect on the off-taste associated withsaccharin,

B. Taurine has a substantial effect on the off-taste of saccharin whileit has little or no effect on the off-taste associated withL-aspartyl-L-phenylalanine methyl ester (Aspartame®).

C. The burning after-taste associated with some liquors can besubstantially eliminated with the use of potassium 2,4-dihydroxybenzoatewhile L-aspartyl-L-phenylalanine and taurine have considerably less ofan effect.

More specific examples of this effect are set forth in the followingtable. The concentrations necessary to obtain these effects aredependent upon the specific tastand and material and vary widely fromexample to example in the table. The effects summarized in the tableprovide a further indication of the existence of different bittertastes. Thus as illustrated, L-aspartyl-L-phenylalanine blocks thebitter taste of KCl but has little effect on the bitterness associatedwith caffeine. In contrast,N-(p-cyanophenylcarbamoyl)-aminomethanesulfonic acid reduces the bittertaste of caffeine but is not effective against the bitter taste of KCl.A plausible conclusion is that separate receptors and/or independentsites on one or more receptor are involved in the bitter tastesensation.

    ______________________________________                                                     REDUCTION                                                                     OF THE TASTE                                                                  ASSOCIATED WITH                                                  SPECIFIC MATERIAL                                                                            KCl     SUCROSE   CAFFEINE                                     ______________________________________                                        AP*            YES     NO        NO                                           TAURINE        YES     NO        NO                                           K-2,4-DHB**    YES     NO        NO                                           N-CN-$-ASP-PHE***                                                                            YES     NO        YES                                          N-NO.sub.2 -$-ASP-PHE****                                                                    YES     NO        YES                                          LACTISOLE***** YES     YES       YES                                          N-CN-$-U-SO.sub.3 ******                                                                     NO      YES       YES                                          ______________________________________                                         where:                                                                        *Laspartyl-L-phenylalanine                                                    **potassium 2,4dihydroxybenzoate                                              ***N(p-cyanophenylcarbamoyl)-L-aspartyl-L-phenylalanine                       ****N(p-nitrophenylcarbamoyl)-L-aspartyl-L-phenylalanine                      *****2(4-methoxyphenoxy)propionic acid                                        ******N(p-cyanophenylcarbamoyl)-aminomethanesulfonic acid.               

It will be clear to anyone skilled in the art that the above table isnot all inclusive as to tastands and/or tastes.

As used herein and in the appended claims, a "taste" shall mean anytaste which is salty, bitter, sweet, sour, alkaline, umami, astringent,tangy, dry, sharp, cool, hot, burning, acidic, spicy, pungent and/ormetallic. Such taste shall include any and all taste(s) as well as anyand all aftertaste(s). Once again this list is not all inclusive as oneskilled in the art would recognize.

As used herein an "eatable(s)" shall mean any material ingested.Eatables shall include, but not be limited, to materials ingested byhumans, other mammals, fish, birds, and other animals.

By the term "substantially tasteless" as used herein and the appendedclaims is meant a compound that has substantially no taste upon initialingestion at the levels that are appropriate to be a tastand. Theaftertaste, if any, is not included in this definition.

By the term "sweetener" as used herein and the appended claims is meantany material which gives a sweet perception, including but not limitedto:

A. monosaccharides, including but not limited to aldoses and ketosesbeginning with trioses, including but not limited to glucose, galactose,and fructose,

B. compounds generically known as sugars, which include but are notlimited to mono-, di- and oligosaccharides including but not limited tosucrose, maltose, lactose, etc,

C. sugar alcohols which include but are not limited to sorbitol,mannitol, glycerol,

D. carbohydrates and polysaccharides which include but are not limitedto polydextrose and maltodextrin,

E. high intensity sweeteners.

As used herein and the appended claims "high intensity sweeteners" shallinclude but are not limited to:

L-aspartyl-L-phenylalanine methyl ester (Aspartame®) and other relateddipeptide sweeteners, saccharin,L-aspartyl-D-alanine-N-(2,2,4,4-tetramethyl thiatan-3-yl)amide(Alitame®),1,6-dichloro-1,6-dideoxy-β-D-fructofuranoysl-4-chloro-4-deoxy-α-D-galactopyranoside(Sucralose®), 6-methyl-1,2,3-oxathiazin-4(3H)-one 2,2-dioxide(Acesulfame®), 6-methyl-1,2,3-oxathiazin-4(3H)-one 2,2-dioxide potassiumsalt (Acesulfame-K®), cyclohexylsulfamic acid (Cyclamate®),N-(L-aspartyl)-N'(2,2,5,5,tetramethylcyclopentanoyl)1,1-diaminoethaneand its related compounds, guanidinium class sweeteners, dihydrochalconeclass sweeteners, stevioside, miraculin and thaumatin, and theirphysiologically acceptable salts. Many more sweeteners are described inthe following publications, which are hereby incorporated by reference:

1. Walters, D. E., Orthoefer, F. T., and DuBois, G. E., (Ed.),"Sweeteners Discovery, and Molecular Design, and Chemoreception," ACSSymposium Series 450, American Chemical Society, Washington, D.C., 1991,and

2. Grenby, T. H., "Progress in Sweeteners," Elsevier Applied ScienceSeries, Elsevier Science Publishing, London and New York, 1989.

The authors recognize that this list, or any other list, is not andcannot be all inclusive.

By the term "low intensity sweetener" as used herein and the appendedclaims is meant any sweetener except a high intensity sweeteners.

By the term "masker" as used herein and the appended claims is meant anyflavorful eatable which is used to cover and/or disguise and/or obscurean undesirable taste. Two examples of eatables which are commonly usedas maskers are sweeteners and spices such as onion, garlic, paprika, redpepper, chili powder, etc.

By the term "low calorie eatable" or "low calorie formulation" as usedherein and the appended claims is meant any eatable in which the eatablehas been purposely formulated for the reduced calorie market. Typicallythis has resulted in greater than twenty-five percent (>25%) of thecalories having been removed from said eatable that would have beenpresent in the regular non-low calorie formulation.

The term "tastand" as used herein and the appended claims means aneatable, except for:

1. the class of compounds shown in the following figure: ##STR1## andthen as applied only to the case of organic bitter, and, 2.L-glutamyl-L-glutamic acid (or salts thereof) which when mixed with orwhen ingested along with another eatable said eatable having anundesirable taste(s), will eliminate or substantially reduce saidundesirable taste(s) without introducing a taste of its own at saidlevel of usage.

Tastands can also be salt tastands. Tastands have the property that theywill block one undesirable taste for example, bitter, and/or in somecases at the same time another undesirable taste. A specific tastand mayhave its own particular taste but its ability to block an undesirabletaste occurs at a concentration below that at which its own particulartaste is perceptible. Tastands may uncover tastes and/or off-tastes thatwere present in the eatable before the addition of the tastand. Atastand will not introduce any substantial taste and/or off-taste of itsown. This property differentiates tastands from masking materials. Forexample to determine if a tastand is a bitter blocker it could be addedto a solution of a bitter material such as KCl. If the material is atastand it will block or substantially reduce the undesirable taste ofKCl before it imparts any significant taste of its own. It is understoodthat a tastand may have the ability to block one undesirable taste moreeffectively than another undesirable taste. Some tastands may block onlyone undesirable taste effectively. A given tastand may, for example,block the perception of bitter at a level of 10-20 ppm but require1000-10,000 ppm in order to effectively block another undesirable tasteand/or tastes or it may not block the perception of another undesirabletaste or tastes at any concentration. This relative effectiveness orinability to block certain tastes at all will vary from tastand totastand and/or with concentration of the same tastand. Some specifictastands may block tastes that are not undesirable in certain specificapplications such as sweet. Some tastands when added to an eatable mayincrease the perception of another taste for example the level ofsaltiness of the eatable. The blocking of an undesirable taste may allowin some cases an increased sensation of another taste. In thisparticular instance the increased salt sensation that is perceived bythe addition of a tastand is allowing the tastand to act as if it were asalt enhancer.

A "salt tastand" as used herein and in the appended claims means atastand which, is itself salty or is combined with another saltyeatable, and when mixed with or when ingested along with an eatablepossessing an undesirable taste will reduce or eliminate the perceivedundesirable taste(s) of said eatable. Examples of such salty eatablesthat could be used with a tastand to make a salt tastand would be NaCl,KCl, or NH₄ Cl.

As used herein and the appended claims many of the tastands and eatablesare molecules named variously as salts and/or acids. It is obvious toone skilled in the art that these terms are arbitrary and virtually anyacid can be a salt and vice versa depending upon the macroenvironmentand/or microenvironment that the molecule is in. This environment can,in some instances, change the efficacy of a particular tastand. Forexample, 2,4-dihydroxybenzoic acid is not nearly as potent a tastand ofthe off-taste of KCl as is potassium 2,4-dihydroxybenzoate. (In somespecific acid environments the potassium 2,4-dihydroxybenzoate may losesome of its effectiveness.) Consequently, throughout the body of thispatent and the appended claims, it should be understood the recitationof acid and/or base refers also to the physiologically acceptable saltsand the recitation of a salt refers to its corresponding acid and/orbase.

The solubility of the tastand in water may not be sufficient todemonstrate the blocking ability. In this case the tastand's solubilitycould be increased by the use of other substances to help this lack ofsolubility. Ethyl alcohol is one example of a material which can be usedto increase the solubility of potential tastands to be used in the abovereferenced tastand test.

Surfactants can affect the tastand by either increasing or decreasingthe effectiveness of the tastand. As used herein and in the appendedclaims, a "surfactant" shall mean an amphipathic molecule. Such surfaceactive agents shall include but not be limited to soaps, and/ordetergents, whether ionic or non-ionic, and/or membrane lipids. Somesurfactants can increase the effectiveness of some tastands while thesame surfactant may lessen the effectiveness of other tastands or notaffect that particular tastand at all. Surfactants may affect eachtastand differently. The surfactant that affects one particular tastandin a positive, negative or neutral sense may affect another tastanddifferently (i.e. a positive, negative or neutral sense and notnecessarily in the same way).

Different transformations, as such term is used hereinbelow, of amaterial may also have a profound effect on its tastand character.

Many of the above tastand principles can be demonstrated with potassium2,4-dihydroxybenzoate (potassium β-resorcylate). This material in aboutone to two percent (1-2%) w/v solution is sweet. When potassium2,4-dihydroxybenzoate is combined with KCl at, for example, 0.25% to0.50% by weight relative to the KCl (depending upon the individual'ssensitivity to bitter) it Will virtually eliminate the bitternessassociated with the potassium chloride. (This means that in an eatablecontaining one percent (1%) KCl the amount of potassium2,4-dihydroxybenzoate that would be needed would be only 25 to 50 ppm.)Potassium 2,4-dihydroxybenzoate is also a tastand for the metallic tasteassociated with saccharin. If 25 to 50 milligrams of potassium2,4-dihydroxybenzoate is added to a can of soda sweetened with saccharin(69 to 138 ppm of potassium 2,4-dihydroxybenzoate relative to the soda)the metallic taste is substantially reduced or eliminated allowing otherflavors in the soda to come through. In the above examples (25-138 ppm)potassium 2,4-dihydroxybenzoate is a tastand because of its ability toblock bitter taste at concentrations where it by itself is substantiallytasteless. Potassium 2,4-dihydroxybenzoate is sweet only atsignificantly higher concentrations. In contrast, sucrose is not atastand in that a 2% solution is sweet but even at this level thebitterness of KCl is not substantially diminished. Sucrose would be amasking material under the current definitions.

The use of additives to debitter eatables has been attempted by others.Recently, a fairly comprehensive approach to this goal was reported in"Practical Debittering Using Model Peptides and Related Compounds" byTamura M., Mori N., Miyoshi T., Koyama, et al in Agric. Biol. Chem. 54,(1) 41-51 (1990). The authors examined the following classes ofcompounds and strategies to debitter solutions of amino acids, aminoacyl sugars and peptides:

A. Chemical modification.

B. Masking agents such as cyclodextrins and starch.

C. Proteins and peptides such as skim milk, soybean casein, whey proteinconcentrate or casein hydrolysates.

D. Fatty substances.

E. Acidic amino acids.

Chemical modification of bitter tasting materials led to reducedbitterness but the materials were not tastands because the chemicalmodifications generally led to derivatives with their own characteristicundesirable taste. Case studies 2-4 were based on a strategy of thedirect interaction of the additive with the undesirable taste componentof an eatable in order to prevent said undesirable taste component fromreaching the bitter taste receptor. In case study 5, the authors usedmolar equivalents of "acidic amino acids" or taurine (the authors statethat, "taurine, of course, is not an acidic amino acid although it has asulfonyl group and shifts to the acidic region") to reduce bitterness.

The paper reports that under the conditions tested, the acidic aminoacids removed some of the bitter taste but conferred their own sourtaste to the test solution. Taurine, according to FIGS. 4 and 5 of thepaper was ineffective at debittering solutions of Arg, Phe,methyl,2,3-di-O-(1-phenylalanyl)-α-D-glycopyranoside, Phe-Phe, orArg-Pro-Phe-Phe at from 0.33 to 1.5 molar equivalents. The results fromFIGS. 4 and 5 are internally inconsistent with respect to valine testedin a solution at the 300 mM level. While FIG. 4 shows a less than fiftypercent (<50%) reduction of bitterness when 0.333 equivalents of taurinewas added to the test solution, FIG. 5 shows >60% reduction when 0.22equivalents of taurine (67 mM) was added to the solution. Theinconsistent result of the taste tests indicate that Tamura did notcontemplate an important teaching of the present invention and led us torepeat the taste test. It is also clear that Tamura did not understandor contemplate the effect that a tastand can have on a taste test. Thisapplication teaches this effect hereinbelow.

As stated above, we have repeated the taste test for valine. This wasdone in a 300 mM solution of valine (conditions of Tamura et al.) atvarious levels of taurine reported in the Tamura paper. The results weobtained were confirmed by an independent testing laboratory. Theindependent test laboratory's results are summarized in the followingtable:

    ______________________________________                                                     MEAN VALUE OF THE                                                CONCENTRATION                                                                              BITTERNESS OF A                                                  OF TAURINE   300 mM SOLUTION OF VALINE                                        ______________________________________                                        CONTROL       9.6                                                             (0 TAURINE)                                                                    66 mM        9.5                                                             200 mM       13.3                                                             300 mM       11.4                                                             ______________________________________                                    

The data show that taurine has virtually no effect on the bitterness ofvaline. When the tasting was repeated with taurine on an equal molarbasis with the valine (three times the amount shown in FIG. 4 of Tamuraand sixteen times that amount shown in FIG. 5), there was still >50% ofthe bitterness remaining in the valine test solution. We did not repeatthe aspartic acid and glutamic acid taste tests as they, under theconditions of Tamura, et al., are not tastands. Even at 300 mM level thepaper shows that taurine was ineffective at "masking of the bitterness"of almost all solutions tested. The high concentrations used in theseinvestigations suggest that the authors intended to mask the bittertaste. The authors did not understand or even contemplate the concept oftastands.

The underlying assumption of any experiment that has a control builtinto the methodology, is that the controls are accurate and repeatable.If blockers are used randomly, the controls are neither accurate norrepeatable. If a so called control is ingested followed by a food with ablocker, the subsequent tasting of the previously ingested control willbe different. If the authors of the Tamura study had realized this theyprobably could have designed the protocols to avoid these problems andthe reported results would have been accurate and repeatable.

In contrast to the above it is the teaching. of the present applicationthat a tastand, as defined hereinabove, can prevent bitter componentsfrom interacting with the taste receptor at concentrations where thetastand is tasteless or substantially tasteless. Prevention is by adirect interaction with the receptor site, as such term is used herein,to prevent or substantially eliminate:

A. the interaction of the undesirable tasting molecule(s) with the tastereceptor and/or

B. the recognition of the undesirable taste. Glenn Roy, Chris Culberson,George Muller and Srinivasan Nagarjan in U.S. Pat. No. 4,944,990 datedFeb. 19, 1991, described the use of N-(sulfomethyl)-N'-arylureas toinhibit or suppress sweet taste and organic bitter when mixed with sweetand/or organic bitter. (The authors specifically state that theirmaterial does not affect the off-taste of inorganic bitter.) The examplethat these authors used to show that there was a perceived bitternessreduction was a 0.11% (1.1 mg/mL) caffeine solution to which 4 mg/mL ofN-(sulfomethyl)-N'-arylurea was added. Even while adding a four hundredpercent (400%) excess of the bitter reducing material compared to thebitter eatable, the Roy et al resulted in only fifty percent (50%)reduction of perceived bitterness.

We have demonstrated that low concentrations (0.05%) of potassium2,4-dihydroxybenzoate can eliminate the bitter aftertaste of KCl and thebitter aftertaste of saccharin. only at much higher concentrations ispotassium 2,4-dihydroxybenzoate sweet tasting. Similarly, according toour thesis, taurine should be a tastand and we have found, in contrastto the teaching of Tamura, et al., that taurine at five percent (5%) (3%on a molar basis) relative to KCl will eliminate or substantially reducethe off-taste of KCl. This would mean that in a one percent (1%)solution of KCl (10 mg/mL) only 0.5 mg/mL of taurine would be needed andif the blocker were potassium 2,4-dihydroxybenzoate only 0.05 mg/mL ofblocker would be needed.

Similarly if ten (10) mg of taurine is added to a can of soda (354 mL ofsoda per can; 28 ppm taurine) sweetened only with saccharin theoff-taste of the saccharin is substantially reduced or eliminated, whilethe sweet taste is relatively unaltered.

The present teaching is analogous to a competitive inhibition with abinding site of the receptor(s) and/or a non-competitive inhibition withthe site(s) that influences the receptor. As such, one of our teachingsis that the tastand can be effective at a low tastand concentration whencompared to the eatable with the undesirable taste. This distinction isnot a minor teaching as in practical terms it would be impossible to addmore of the debittering material than the bitter materials. If theTamura paper's lower level of proposed use for taurine (0.5 equivalentsof taurine) is added to a one percent (1%) KCl solution, the resultantsolution has a pronounced off-taste which was not present when only 0.03equivalents (0.5% by weight relative to the KCl) was used. (If even thelowest level of taurine which was proposed in the Tamura paper is addedto water, the water has an off-taste.) The off-taste of the taurine whenadded to the KCl solution is even more pronounced at the 1.0 and 1.5equivalent levels reported in the paper. Taurine is not a tastand at theusage levels proposed in the Tamura article. The Tamura article gives noindication that reducing the levels to 1/5 to 1/100 of their proposedlevels will give better and more desirable taste test results.

According to the authors of the above referenced Tamura article the"debittering of peptides did not seem to work." The authors thereconcluded "However, even 1.5 equivalent of acidic amino acids did notwork. Probably, we have to discuss elsewhere the order of attachment oftaste functional groups to taste receptors sites."

The teachings in this application clearly show that the debittering ofpeptides does work. If five (5) to seven and one half (71/2) mg ofL-aspartyl-L-phenylalanine is added to a soda sweetened only withL-aspartyl-L-phenylalanine methyl ester (Aspartame®) (354 mL of soda percan (14 to 21 ppm)) the off-taste of the L-aspartyl-L-phenylalaninemethyl ester (Aspartame®) is reduced or substantially eliminated. TheL-aspartyl-L-phenylalanine that is added as a tastand to the materialsweetened with the L-aspartyl-L-phenylalanine methyl ester (Aspartame®)is in addition to the amount of L-aspartyl-L-phenylalanine that may ormay not be present from the breakdown product of theL-aspartyl-L-phenylalanine methyl ester (Aspartame®) or as amanufacturing impurity. The use of L-aspartyl-L-phenylalanine as atastand is an unanticipated result that was not previously known orcontemplated. In fact while L-aspartyl-L-phenylalanine is one of thebreakdown products of L-aspartyl-L-phenylalanine methyl ester(Aspartame®), the breakdown of the L-aspartyl-L-phenylalanine methylester (Aspartame®) has not been considered a desirable occurrence. Boththe manufacturers and users of the L-aspartyl-L-phenylalanine methylester (Aspartame®) go to great lengths to prevent this degradation. Theyattempt to do this by adjusting the formulations of the products inwhich the material is used. In addition, in the case of the manufacturerthe undesirable breakdown of the product can be slowed down by sellingthe material in a dry state, as well as by the purification of thematerial. (When L-aspartyl-L-phenylalanine is present as a manufacturingimpurity it is typically present in an amount less than one percent(<1%) of the L-aspartyl-L-phenylalanine methyl ester.) The above exampleof the addition of five (5) to seven and one half (71/2) mg ofL-aspartyl-L-phenylalanine would be about four percent (4%) of theL-aspartyl-L-phenylalanine methyl ester that has been used to sweetenthe soda. Examples of the products that could be found from thebreakdown of the L-aspartyl-L-phenylalanine methyl ester in the soda areα-L-aspartyl-L-phenylalanine, β-L-aspartyl-L-phenylalanine, methanol,L-aspartyl-L-phenylalanine diketopiperazine, L-phenylalanine, L-asparticacid, L-phenylalanine methyl ester and β-L-aspartyl-L-phenylalaninemethyl ester. The ratio of these and other possible breakdown productswill vary according to the conditions of storage (time and temperature)as well as the soda's specific composition its pH, etc.) The presentinvention teaches the use of the breakdown products, whether suchbreakdown occurs deliberately or accidently, of theL-aspartyl-L-phenylalanine methyl ester (Aspartame®) into one or moretastand(s). Another example of a breakdown product of theL-aspartyl-L-phenylalanine methyl ester (Aspartame®) that is a tastandis β-L-aspartyl-L-phenylalanine.

If the soda is sweetened with both L-aspartyl-L-phenylalanine methylester (Aspartame®) and saccharin then two tastands may be needed toreduce or substantially eliminate the off-taste of the two highintensity sweeteners. For example both taurine andL-aspartyl-L-phenylalanine could be used. The levels of the tastandsthat would be needed would depend on the relative levels of the highintensity sweeteners that were used in the soda.

Combination of tastands are sometimes preferred. On potato chips, a saltconsisting of a ratio of eighty percent (80%) KCl and twenty percent(20%) NaCl with taurine at five percent (5%) relative to the KCl andthree percent (3%) L-aspartyl-L-phenylalanine is sometimes preferred toa single tastand. Such single tastand could be for example taurine,L-aspartyl-L-phenylalanine or potassium 2,4-dihydroxybenzoate.

The results of our tastings have confirmed that any methodology thatemploys a random presentation of eatables both with and without blockersis flawed because the random presentation of eatables with and withoutblockers causes the "controls" to move. The taste evaluation of thecontrols will be altered by the use of the blockers in the samerandomized tasting. This "moving" of the controls will occur because theblockers are consumed before the eatables that do not contain theblockers. (If an eatable that was found to be bitter in a previouslyconducted taste test were presented to the panelist at or near the endof the tasting that contained a tastand, the typical result would bethat the previously bitter food is no longer nearly as bitter.) In sometests conducted inca randomized manner, pure KCl foods, for example,which were earlier determined to be very bad, bitter and metallic,during the first round of testing, were then determined to be almost asgood tasting as NaCl foods when tasted at or near the end of thetasting.

The qualities of tastands described throughout this document are insharp contrast to those of gymnemic acid as reported in The Merck Index(Eleventh Edition, 1989) (hereinafter "Index") where it is stated thatgymnemic acid "Completely obtunds taste for several hours for bitter orsweet, . . . " (This description of the properties of gymnemic acid isnot entirely consistent with the articles that were quoted for thisinformation in the Index, one of which states, "After chewing one or twoleaves one is unable to detect the sweet taste, and the bitter taste isalso suppressed to some extent.") (emphasis added) The Index also statesthat gymnemic acid is a bitter tasting compound. More recentpublications that have used purified gymnemic acid A₁ and A₂ have shownthat there is a profound effect on the sweet response that is stillpresent after more than fifteen minutes. These reports state that thereis no effect on the bitter response. The reports do not comment on thetaste of gymnemic acid A₁ and A₂, nevertheless gymnemic acid is not atastand under the definition contained herein.

An abundance of literature exists on the study of the perception oftaste, particularly in the area of sweet taste. Over the past twodecades, numerous researchers have attempted to develop new non-caloricsweeteners. This work began in earnest following the introduction ofAspartame® (L-aspartyl-L-phenylalanine methyl ester) several years ago.As a result of this work, a large variety of sweet molecules are nowknown.

There has been a substantial amount of work on the perception of sweettaste, as well as on the interaction of molecules with the receptor forsweet taste. All of this work points to the fact that the sweet receptorand the bitter receptor as well as the other taste receptors may be inclose proximity and/or related to one another and/or possibly one andthe same. It is now known, for example, that if sweet molecules arealtered slightly, particularly in their spatial arrangements and/ororientation and/or configuration of their chiral centers and/or theirstereochemistry and/or by the addition or substitution and/orelimination in the molecule of various groups, that such molecules maybecome bitter or tasteless. Throughout this document the alteration of amolecule in its spatial arrangements and/or orientation and/orconfiguration of its chiral centers and/or its stereochemistry and/or bythe addition or substitution and/or elimination in the molecule ofvarious groups, will hereinafter be referred to as "transformation(s)".Sometimes the transformation of a molecule that:

A. is a tastand will change said molecule into a molecule that is a moreactive tastand or less active tastand or not a tastand at all, or

B. is not a tastand will change it to a tastand.

Such transformations in a molecule may change the molecule from any oneof these (sweet, bitter or tasteless) to any of the following: sweet,bitter or tasteless.

Consequently, it occurred to us that:

A. the perception of sweet and the perception of bitter may beassociated with the same receptor, part of the same receptor, veryclosely spatially related receptors or separate receptors which acttogether to give the associated sweet or bitter taste response, and

B. that the perception of undesirable tastes may be associated with thissame receptor, part of this same receptor or very closely spatiallyrelated receptors or separate receptors which act together to give theassociated undesirable taste.

(all concepts relating to the receptor(s) are herein referred to as"receptor site(s)" or "receptor(s)").

This transformation feature is well illustrated in the case of thedipeptide-like sweeteners. For instance, L-aspartyl-L-phenylalaninemethyl ester (Aspartame®) is intensely sweet. Whereas,L-aspartyl-L-phenylalanine methylamide is intensely bitter andL-aspartyl-L-phenylalanine free acid is tasteless. ##STR2## Thesetransformations extend to almost all of the known dipeptide classes ofsweeteners, including the aspartyl-D-alanine amides where many of theaspartyl-D-alanine alkylamides are sweet and many of the correspondingL-amides are bitter. A similar set of examples exist for the aminomalonic acid derivatives, the aspartyl alanine esters and most otherclasses of peptide-like sweetener compounds. Transformations also extendto many other classes of compounds. For example, in the saccharin typemolecules the presence or absence of nitration or alkylation can lead toa molecule that is tasteless or sweet or bitter. This is illustrated inthe following example: ##STR3##

Another example of a transformation can be seen in the substitutedpropoxybenzenes where the position, the location and the number of theNH₂ and the NO₂ substituents determine if the molecule is tasteless orsweet and/or bitter. This is illustrated in the following example:##STR4##

Another example of a transformation can be seen in the substitutedethoxybenzenes. ##STR5##

Another example of a transformation can be seen in the following:##STR6##

Such transformations can be extended to most classes of sweet or bittertasting substances. Consequently it is likely that a non-sweet analogueof thaumatin (a large peptide) exists which would be a tastand. Ingeneral most sweet or bitter eatables should be able to be transformedinto a tastand regardless of the size or chemical structure. Inaddition, polymeric substances, as well as di-, oligo-, and poly-peptidesubstances would also be anticipated by the present disclosure. Thesefacts lead us to the conclusion:

A.

1. if a molecule possessed similar spatial arrangements to knownsweeteners; and

2. with slight alterations the molecule could be made substantiallytasteless

B.

1. if a molecule possessed similar spatial arrangements to a knownbitter substance; and

2. with slight alterations the molecule could be made substantiallytasteless

that such molecules should interact with the receptor in the same way asweet or bitter tasting molecule would interact but without theassociated taste. If this occurs, then this substantially tastelessmolecule should inhibit the entrance of other molecules into thereceptor.

Consequently, we concluded and discovered the following:

A. If the molecule is a tastand, it may inhibit or reduce the sweetnessof substances, and in some instances it will also inhibit or reduceundesirable tastes; and/or

B. If the molecule is a tastand, it may inhibit or reduce the bitternessof substances, and in some instances it will also inhibit or reduceother undesirable tastes; and/or

C. If a sweet molecule can be spatially altered to become substantiallytasteless, this molecule will likely be a tastand; and/or

D. If a bitter molecule can be spatially altered to become substantiallytasteless, this molecule will likely be a tastand.

In addition, it has been found that when an eatable possesses desirablecharacteristics, for example, a salty taste, these desirablecharacteristics may not be inhibited or adversely affected by thetastand inhibitors of the invention.

In addition, in order to achieve a desired degree of reduction and/orelimination of undesirable taste(s), it has been found that more thanone tastand might be needed in some cases. If more than one tastand isnecessary, then it would be obvious to one skilled in the art to eitherhave each one of the tastands ingested in a temporally appropriatemanner and/or to chemically link the tastands. In the case of chemicallylinked tastands the basic molecule could be linked with one or moresimilar or dissimilar tastand molecule(s).

In addition, synergism of molecules in some cases may allow two or moremolecules, that in and of themselves do not appear to be tastands, toact as a tastand when said molecules are used in a temporallyappropriate manner.

It has further been found that many of the tastands will block orinhibit the undesirable taste(s) of, to mention a few examples,potassium chloride, potassium glutamate, potassium benzoate, potassiumnitrate, potassium nitrite, potassium sulfate, potassium sulfite,potassium baking powder and potassium baking soda (which probably becomepotassium chloride or other potassium salts after baking), aspirin,acetaminophen, antibiotics, codeine, caffeine, unsweetened chocolate,other medicaments or other undesirable taste(s) of the eatable.

Some tastands have also been found to enhance salt taste. Thus tastandscan be used in conjunction with mixtures of substances with undesirabletastes such as, for example, potassium chloride and/or sodium chlorideand/or ammonium chloride to both reduce the undesirable taste(s) and toenhance the salt taste of the sodium and/or potassium and/or ammoniumchloride.

Eatables which are not generally considered to have an undesirable tastecould also benefit from the addition of an appropriate tastand as ataste modifier. For example:

A. Sodium chloride, which is normally not considered bitter, issubstantially smoothed in its aftertaste with the addition of theappropriate tastand.

B. A smoothing effect can be achieved when a tastand is added to plainunflavored, unsweetened yogurt which is normally considered tangy oracidic tasting.

C. The bitter taste of coffee can be substantially reduced or eliminatedwith the addition of the appropriate tastand.

D. The burning sensation of hard liquors can be reduced or eliminatedwith the addition of the appropriate tastand.

In the case of sour materials such as lemon juice when the appropriatetastand and/or salt tastand is added there is a substantial change inthe undesirable taste. This is especially true if a salt, such aspotassium or sodium chloride, is added to the tastand. If a salt tastandis added, the undesirable taste can be reduced or even eliminated.

As used herein and the appended claims the singular and the plural of adefined term shall be one and the same. As used herein and the appendedclaims defined terms with and without initial capitalization shall meanone and the same.

DETAILED DESCRIPTION OF THE INVENTION Tastands Molecules as TasteModifiers

The tastands useful in the present invention are those compounds of theprior art which are tastands that are substantially tasteless. In manyinstances, substances of the prior art which could be tastands which arenot tasteless can be rendered substantially tasteless bytransformation(s).

As used herein and the appended claims, "Group 1" substituents may berepresented by:

H, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl,substituted aryl, alkylene, substituted alkylene, aminoacyl, substitutedaminoacyl, aryloxy, substituted aryloxy, hydroxy, nitro, amino,substituted amino, cyano, halogen, aralkoxy, substituted aralkoxy, acyl,substituted acyl, arylacyl, substituted arylacyl, trifluoroacetyl,benzoyl, substituted benzoyl, alkylamino, substituted alkylamino,dialkylamino, substituted dialkylamino, trialkylamino, substitutedtrialkylamino, carbonates, substituted carbonates, alkylcarbonates,substituted alkylcarbonates, arylcarbonates, substituted arylcarbonates,acylamino, substituted acylamino, guanidino, substituted guanidino,alkylguanidino, substituted alkylguanidino, acylguanidino, substitutedacylguanidino, arylguanidino, substituted arylguanidino, alkyurethanes,substituted alkyurethanes, arylurethanes, substituted arylurethanes,ureas, substituted ureas, mono- or di- or tri-substituted ureas,alkylureas, substituted alkylureas, an O, S or N glycoside, or aphosphorylated glycoside (where the glycoside is a monosaccharide, adisaccharide, a trisaccharide, an oligosaccharide, a substituted mono-,di-, tri-, or oligosaccharide), CHO, substituted CHO, COCH₃, substitutedCOCH₃, CH₂ CHO, substituted CH₂ CHO, COOH, CH₂ COOH, substituted CH₂COOH, COOCH₃, substituted COOCH₂, OCOCH₃, substituted OCOCH₃, CONH₂,substituted CONH₂, NHCHO, substituted NHCHO, SCH₃, substituted SCH₃,SCH₂ CH₃, substituted SCH₂ CH₃, CH₂ SCH₃, substituted CH₂ SCH₃, SO₃ H,SO₂ NH₂, substituted SO₂ NH₂, SO₂ CH₃, substituted SO₂ CH₃, CH₂ SO₃ H,substituted CH₂ SO₃ H, cycloalkyl, substituted cycloalkyl, heterocyclic,substituted heterocyclic, polycyclic, substituted polycyclic, and CH₂SO₂ NH₂, arylureas, substituted arylureas, multiple substitutedarylureas, an acid group of the structure ZO_(q) H_(r) wherein Z is anelement selected from the group consisting of carbon, sulfur, boron orphosphorus, q is an integer from 2 to 3 and r is an integer from 1 to 3;carboxylic acid ester, substituted carboxylic acid ester, carboxamide,substituted carboxamide, N-alkyl carboxamide, substituted N-alkylcarboxamide, di-alkyl carboxamides, substituted di-alkyl carboxamides,and/or two substituents together represent an aliphatic chain linked toa phenyl ring at two positions, either directly or via a an oxygen,nitrogen or sulfur group, any H on N, S, or O, may be substituted withone of the substituents of Group 2,

and combinations of any and/or all of the foregoing, and physiologicallyacceptable salts of any and/or all of the foregoing.

As used herein and the appended claims "Group 2" substituents may berepresented by:

H, alkyl, substituted alkyl, dialkyl, substituted dialkyl, aralkyl,substituted aralkyl, aryl, substituted aryl, diaryl, substituted diaryl,acyl, substituted acyl, cycloalkyl, substituted cycloalkyl, benzoyl,substituted benzoyl, trifluoroacetyl, alkyloxycarbonyl, substitutedalkyloxycarbonyl, aryloxycarbonyl, substituted aryloxycarbonyl,alkylaminocarbonyl, substituted alkylaminocarbonyl, arylaminocarbonyl,substituted arylaminocarbonyl, amidines, substituted amidines,alkylamidines, substituted alkylamidines, arylamidines, substitutedararylamidines, a monosaccharide, substituted a monosaccharide, adisaccharide, substituted disaccharide, a trisaccharide, substitutedtrisaccharide, an oligosaccharide, substituted oligosaccharide,phosphorylated saccharides, substituted phosphorylated saccharides,arylacyl, substituted arylacyl, alkylene, substituted alkylene,heterocyclic, substituted heterocyclic, polycyclic, substitutedpolycyclic, cyano, nitro, any H on N, S, or O, may be substituted withone of the above substituents,

and combinations of any and/or all of the foregoing and physiologicallyacceptable salts of any and/or all of the foregoing.

As used herein and the appended claims "Group 3" substituents may berepresented by:

H, alkyl, substituted alkyl, alkylene, substituted alkylene, branchedalkyl, substituted branched alkyl, branched alkylene, substitutedbranched alkylene, aryl, substituted aryl, aralkyl, substituted aralkyl,cycloalkyl, substituted cycloalkyl, acyl, substituted acyl, benzoyl,substituted benzoyl, alkoxy, substituted alkoxy, aryloxy, substitutedaryloxy, trifluoromethyl, halogen, cyano, heterocyclic, substitutedheterocyclic, polycyclic, substituted polycyclic, hydroxy, amino,substituted amino, sulfydryl, substituted sulfydryl, an O, S or Nglycoside, or a phosphorylated glycoside (where the glycoside is amonosaccharide, a disaccharide, a trisaccharide, an oligosaccharide, asubstituted mono-, di-, tri-, or oligosaccharide),

and combinations of any and/or all of the foregoing.

As used herein and the appended claims "substituted" indicates that themolecule may have any hydrogen atom replaced or "substituted" by any ofthe substituents of Groups 1, 2 or 3, in any combination.

As used herein and the appended claims specific tastands containingacidic or basic groups shall include all physiologically acceptablesalts thereof as well as the free acid and/or base as is appropriate.

As used herein and the appended claims specific tastands containingcarbon-carbon mono, double or triple bonds may be reduced or oxidized togive carbon-carbon mono, double or triple bonds.

As used herein and the appended claims any aromatic molecule in Groups1, 2 or 3 above may be substituted with one of the substituents of Group1.

It would be understood by one skilled in the art that any substituentnot specifically defined is H.

It is understood by those skilled in the art that only thesubstitutions, replacements, oxidations, reductions and descriptionsabove, allowed by the laws of chemistry, physics and nature arecontemplated for use as tastands as described in the classes ofcompounds below.

Illustrative of suitable classes of molecules contemplated for use astastands are the following:

A. As used herein and the appended claims the following molecule shallbe referred to as A-1 and said molecule represents the general class ofcompounds having the structure: ##STR7## wherein m represents 0 or 1, nrepresents 0, 1, 2 or 3, p represents 1, 2, 3, 4 or 5, q represents 0 or1; any R is represented independently by one of the substituents ofGroup 3; the substituents R', which may be the same or different, areeach represented by one of the substituents of Group 1, in anycombination; and in addition where CH--CH or CH₂ --CH₂ bonds exist thelevel of unsaturation may be increased. X⁺ represents H⁺ or aphysiologically acceptable cation,

and physiologically acceptable salts of any and/or all of the foregoing.

Some specific compounds within this class of tastands and theirpreparation are described in U.S. Pat. No. 4,567,053 and are herebyincorporated by reference.

Examples of compounds of particular interest within this class are:

1. (-)-2-(4-methoxyphenoxy)propionic acid,

2. (±)-2-(4-methoxyphenoxy)propionic acid,

3. (+)-2-(4-methoxyphenoxy)propionic acid,

4. 4-methoxyphenoxyacetic acid,

5. 2-(4-methoxyphenyl)propionic acid,

6. 2-(4-ethoxyphenoxy)propionic acid,

7. 3-(3,4-dimethoxyphenoxy)propionic acid,

8. 3-(3,4-dimethoxyphenyl)propionic acid,

9. 3-(2,3,4-trimethoxyphenoxy)propionic acid,

10. 3-(2-methoxyphenyl)propionic acid,

11. 1,4-benzodioxan-6-acetic acid,

12. 3-(2,3,4-trimethoxyphenyl)propionic acid,

13. 3-(3,4,5-trimethoxyphenyl)propionic acid,

14. 3-(4-methoxyphenyl)propionic acid,

15. 4-(4-methoxyphenyl)butyric acid,

16. 2-methoxyphenylacetic acid,

17. 3-methoxyphenylacetic acid,

18. 4-methylphenylacetic acid,

19. 4-trifluoromethylphenylacetic acid,

20. phenylpyruvic acid,

21. 2,3-dihydroxybenzoic acid,

22. 2-hydroxy-4-aminobenzoic acid,

23. 3-hydroxy-4-aminobenzoic acid,

24. phenoxyacetic acid,

25. gallic acid,

26. 2,4-dihydroxybenzoic acid,

27. 2,4-dihydroxyphenylacetic acid,

28. 2-(2,4-dihydroxyphenyl)propionic acid,

29. 2-(2,4-dihydroxyphenoxy)propionic acid,

30. 2-(2,4-dihydroxyphenoxy)acetic acid,

and the physiologically acceptable salts of any and/or all of theforegoing.

B. As used herein and the appended claims the following molecule shallbe referred to as B-1 and said molecule represents the general class ofcompounds having the structure: ##STR8## wherein R₇ and R₈ may beindependently selected from the one of the substituent of Group 3 in anycombination; and in addition where CH--CH or CH₂ --CH₂ bonds exist thelevel of unsaturation may be increased and wherein R₁, is the group, (asused herein and the appended claims the structure shall be referred toas B-2): ##STR9## wherein R₂, R₃, R₄, R₅ and R₆ are independentlyselected from the substituents of Group 1, in any combination,

and physiologically acceptable salts of any and/or all of the foregoing.

Some specific compounds within this class of tastands are described inU.S. Pat. No. 4,544,565 and are hereby incorporated by reference.

Illustrative members of particular interest in this class include:

1. 3-(3'-4'dimethylbenzoyl)propionic acid,

2. 3-(2',4'-dimethylbenzoyl)propionic acid,

3. 3-(2'-methyl-4'-ethylbenzoyl)propionic acid,

4. 3-(2',4',6'-trimethylbenzoyl)propionic acid,

5. 3-(4'-carboxybenzoyl)propionic acid,

6. 3-(4'-hydroxybenzoyl)propionic acid,

7. 3-(3'-methyl-4'-hydroxybenzoyl)propionic acid,

8. 3-(2',4'-dihydroxybenozoyl)propionic acid,

9. 3-(2',4'-dihydroxy-6'-methylbenzoyl)propionic acid,

10. 3-(3'-methyl-4'-ethoxybenzoyl)propionic acid,

11. 3-(3'-ethyl-4'-ethoxybenzoyl)propionic acid,

12. 3-(4'-methoxybenzoyl)propionic acid,

13. 3'-(4'-ethoxybenzoyl)propionic acid,

14. 3-(3',4'-dimethoxybenzoyl)propionic acid

15. 3-(4'-methoxybenzoyl)propionic acid

16. 3-(4'-methoxybenzoyl)-2-methylpropionic acid

17. 3-(4'-methoxybenzoyl)-3-methylpropionic acid,

18. 3',4'-dimethoxybenzoyl-2,3-dimethylpropionic acid,

and physiologically acceptable salts of any and/or all of the foregoing.

C. As used herein and the appended claims the following molecule shallbe referred to as C-1 and said molecule represents the general class ofcompounds having the structure: ##STR10## wherein R¹, R², R³, R⁴, R⁵ andR⁶ are individually represented by one of the substituents of Group 1,in any combination,

and physiologically accepted salts of any and/or all of the foregoing.

Some specific members of this class of tastands are partially describedin U.S. Pat. No. 4,871,570 and are hereby incorporated by reference.

Illustrative members of particular interest in this class include:

1. R² =R³ =R⁵ =R⁶ =H, R¹ =OC₂ H₅, R⁴ =NH--CO--NH₂,

2. R¹ =OCH₂ CH₂ CH₃, R² =NO₂, R⁴ =NH₂, R³ =R⁵ =R⁶ =H,

3. R¹ =CH₃, R² =NH₂, R⁶ =NO₂, R³ =R⁴ =R⁵ =H,

4. R¹ =CH₃, R² =NO₂, R⁴ =NH₂, R₃ =R⁵ =R⁶ =H,

5. 3,4-dihydroxybenzoic acid (protocatechuic acid),

6. 2,4-dihydroxybenzoic acid,

7. 3-hydroxy-4-methoxybenzoic acid,

8. 3,5-dihydroxybenzoic acid,

9. 2,3-dihydroxybenzoic acid,

10. 2-hydroxy-4-aminobenzoic acid,

11. 3-hydroxy-4-aminobenzoic acid,

12. 2,4,6-trihydroxybenzoic acid,

13. 2,6-dihydroxybenzoic acid,

14. 2-amino tere-phthalic acid

and physiologically acceptable salts of any and/or all of the foregoing.

D. As used herein and the appended claims the following molecule shallbe referred to as D-1 and said molecule represents the general class ofcompounds having the structure: ##STR11## wherein n and k independentlymay be 0, 1 or 2; Y (which may be the same or different) may be N(nitrogen), O (oxygen), or S (sulfur); Q may be represented by one ofthe substituents of Group 3; p and q are 1 when Y is O and p and q maybe independently 1 or 2 when Y is S and p and q may be independently 2or 3 when Y is N; R (which may be the same or different when p>1) and R'(which may be the same or different when q>1) are represented by one ofthe substituents of Group 2 or one of the following three structures (asused herein and the appended claims the structures shall be referred toas D-2) in any combination and the appropriate stereochemistry:##STR12## wherein Z and Z' are the same or different and are representedby OH, --O⁻ X⁺, OR", NH₂, NHR", N(R")_(2') ; R" may be alkyl, branchedalkyl, aryl, aralkyl, alkaryl, cycloalkyl, substituted alkyl,substituted cycloalkyl substituted aryl, substituted aralkyl,substituted alkaryl, and R'" may be alkyl, branched alkyl, aryl,aralkyl, alkaryl, cycloalkyl, substituted alkyl, substituted cycloalkyl,substituted aryl, substituted aralkyl, substituted alkaryl, or an aminoacid side chain (e.g. one of the 20 common amino acids); and in additionwhere CH--CH or CH₂ --CH₂ bonds exist the level of unsaturation may beincreased. X⁺ may be H⁺ or a physiologically acceptable cation,preferably an alkali metal, alkaline earth metal or ammonium cation,

and physiologically acceptable salts of any and/or all of the foregoing.

Illustrative of compounds of particular interest in this class are:

1. L-aspartyl-L-phenylalanine,

2. aminomalonyl-L-phenylalanine,

3. L-aspartyl-D-alanine,

4. L-aspartyl-D-serine,

5. L-glutamyl-L-phenylalanine,

6. N-(L-aspartyl)-p-aminobenzoic acid,

7. N-(L-aspartyl)-o-aminobenzoic acid,

8. L-aspartyl-L-tyrosine,

9. N-(p-cyanophenylcarbamoyl)-L-aspartyl-L-phenylalanine,

10. N-(p-nitrophenylcarbamoyl)-L-aspartyl-L-phenylalanine,

11. L-β-aspartyl-L-phenylalanine methyl ester,

12. L-aspartyl-p-hydroxyanilide,

13. L-β-aspartyl-L-phenylalanine

14. L-aspartyl-L-serine methyl ester

15. L-aspartyl-D-tyrosine methyl ester

16. L-aspartyl-L-threonine methyl ester

17. L-aspartyl-L-aspartic acid

and physiologically acceptable salts of any and/or all of the foregoing.

E. As used herein and the appended claims the following molecule shallbe referred to as E-1 and said molecule represents the general class ofcompounds having the structure: ##STR13## wherein R', R", R'", R⁶ areeach independently represented by one of the substituents of Group 2, inany combination; R⁴ 's and R⁵ 's which may be the same or different areeach independently represented by one of the substituents of Group 3; nmay be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; Z may be C, S, P or B, q isan integer from 2 to 3 and r is an integer from 1 to 3, when Z is C, qis 2; when Z is S, P or B, q may be 2 or 3; when Z is C or S, r is 1;when Z is P or B, r is 2; and in addition where CH--CH or CH₂ --CH₂bonds exist the level of unsaturation may be increased,

and physiologically acceptable salts of any and/or all of the foregoing.

Illustrative of compounds of particular interest in this class are:

1. R"=CH₃, R'"=4-cyanophenyl, R'=R⁴ =R⁵ =H, n=1, Z=C, q=2, r=1,

2. R"=CH₃, R'"=4-nitrophenyl, R'=R⁴ =R⁵ =H, n=1, Z=C, q=2, r=1,

3. R"=CH₃, R'"=4-methoxyphenyl, R'=R⁴ =R⁵ =H, n=1, Z=C, q=2, r=1,

4. R"=CH₃, R'"=phenyl, R'=R⁴ =R⁵ =H, n=1, Z=C, q=2, r=1,

5. R"=H, R'"=4-cyanophenyl, R'=R⁴ =R⁵ =H, n=1, Z=C, q=2, r=1,

6. R"=H, R'"=4-nitrophenyl, R'=R⁴ =R⁵ =H, n=1, Z=C, q=2, r=1,

7. R"=H, R'"=4-methoxyphenyl, R'=R⁴ =R⁵ =H, n=1, Z=C, q=2, r=1,

8. R"=H, R'"=phenyl, R'=R⁴ =R⁵ =H, n=1, Z=C, q=2, r=1,

9. R"=CH₃, R'"=4-cyanophenyl, R'=R⁴ =R⁵ =H, n=1, Z=S, q=3, r=1,

10. R"=CH₃, R'"=4-nitrophenyl, R'=R⁴ =R⁵ =H, n=1, Z=S, q=3, r=1,

11. R"=CH₃, R'"=4-methoxyphenyl, R'=R⁴ =R⁵ =H, n=1, Z=S, q=3, r=1,

12. R"=CH₃, R'"=phenyl, R'=R⁴ =R⁵ =H, n=1, Z=S, q=3, r=1,

13. R"=H, R'"=4-cyanophenyl, R'=R⁴ =R⁵ =H, n=1, Z=S, q=3, r=1,

14. R"=H, R'"=4-nitrophenyl, R'=R⁴ =R⁵ =H, n=1, Z=S, q=3, r=1,

15. R'=H, R'"=4-methoxyphenyl, R'=R⁴ =R⁵ =H, n=1, Z=S, q=3, r=1,

16. R"=H, R'"=phenyl, R'=R⁴ =R⁵ =H, n=1, Z=S, q=3, r=1,

and physiologically acceptable salts of any and/or all of the foregoing.

F. As used herein and the appended claims the following molecule shallbe referred to as F-1 and said molecule represents the general class ofcompounds having the structure: ##STR14## wherein n may be 0, 1 or 2; Y(which may be the same or different) may be N (nitrogen), O (oxygen), orS (sulfur); Q may be represented by one of the substituents of Group 3;p and q are 1 when Y is O and p and q may be independently 1 or 2 when Yis S and p and q may be independently 2 or 3 when Y is N; R (which maybe the same or different when p>1) and R' (which may be the same ordifferent when q>1) are represented by one of the substituents of Group2 or one of the following three structures (as used herein and theappended claims the strucutres shall be referred to as F-2) in anycombination and the appropriate stereochemistry: ##STR15## wherein Z andZ' are the same or different and are represented by OH, --O⁻ X⁺, OR",NH₂, NHR", N(R")_(2') ; R" is alkyl, branched alkyl, aryl, aralkyl,alkaryl, cycloalkyl, substituted alkyl, substituted cycloalkylsubstituted aryl, substituted aralkyl, substituted alkaryl, and R'" isalkyl, branched alkyl, aryl, aralkyl, alkaryl, cycloalkyl, substitutedalkyl, substituted cycloalkyl, substituted aryl, substituted aralkyl,substituted alkaryl, or an amino acid side chain (e.g. one of the 20common amino acids); and in addition where CH--CH or CH₂ --CH₂ bondsexist the level of unsaturation may be increased. X⁺ may be H⁺ or aphysiologically acceptable cation, preferably an alkali metal, alkalineearth metal or ammonium cation

and physiologically acceptable salts of any and/or all of the foregoing.

Illustrative of compounds of particular interest in this class are:

1. L-methionyl-L-phenylalanine methyl ester,

2. L-leucyl-L-phenylalanine methyl ester,

3. L-seryl-L-phenylalanine methyl ester,

4. L-methionyl-D-alanyl-tetramethylcyclopentylamide,

5. L-seryl-D-alanyl-tetramethylcyclopentylamide,

6. L-leucyl-D-alanyl-tetramethylcyclopentylamide,

7. L-ornithyl-β-alanine

8. L-diaminobutyryl-β-alanine

9. L-diaminopropionyl-β-alanine

10. L-lysyl-β-alanine

and physiologically acceptable salts of any and/or all of the foregoing.

G. As used herein and the appended claims the following molecule shallbe referred to as G-1 and said molecule represents the general class ofcompounds having the structure: ##STR16## wherein p may be 1, 2, 3, 4,or 5; the substituents R¹ may each be represented by one of thesubstituents of Group 1, in any combination, and R² may be representedby one of the substituents of Group 2,

and physiologically acceptable salts of any and/or all of the foregoing.

Illustrative of compounds of particular interest in this class arecompounds where R² =H and R¹ is:

1. 3-COOH,

2. 3-COOCH₃,

3. 3-COOC₂ H₅,

4. 3-CH₃ O,

5. 4-CH₃ O,

6. 2-Cl,

7. 3-Cl,

8. 4-Cl,

9. 4-COOC₂ H₅,

10. 3-C₆ H₅ CH₂ O,

11. 4-C₆ H₅ CH₂ O,

12. 2-t-butyl,

13. 4-t-butyl,

14. 2-CH₃,

15. 3-CH₃,

16. 4-CH₃,

17. 3-C₂ H₅,

18. 4-C₂ H₅,

19. 3,5-di CH₃,

and physiologically acceptable salts of any and/or all of the foregoing.

H. As used herein and the appended claims the following molecule shallbe referred to as H-1 and said molecule represents the general class ofcompounds having the structure: ##STR17## wherein R¹ is 5-tetrazol orone of the substituents of Group 3, p may be 1, 2, 3, or 4; and thesubstituents R², which may be the same or different, may each berepresented by one of the substituents of Group 1, in any combination;and R³ is represented by one of the substituents of Group 2; and inaddition where CH--CH or CH₂ --CH₂ bonds exist the level of unsaturationmay be increased, and where C═C bonds exist, the level of saturation maybe decreased,

and physiologically acceptable salts of any and/or all of the foregoing.

Illustrative of compounds of particular interest in this class are:

1. 1-α-5-tetrazolyl-6-chlorotryptamine,

2. 1-α-5-tetrazolyl-6-fluorotryptamine,

3. 1-α-5-tetrazolyl-6-methoxytryptamine,

and physiologically acceptable salts of any and/or all of the foregoing.

I. As used herein and the appended claims the following molecule shallbe referred to as I-1 and said molecule represents the general class ofcompounds having the structure: ##STR18## wherein p and q may beindependently 1, 2, 3, 4, or 5; and the substituent R¹ and R², which maybe the same or different, each may be represented by one of thesubstituents of Group 1, in any combination, and the substituent R³, R⁴,R⁵ and R⁶, which may be the same or different, each may be representedby one of the substituents of Group 3, in any combination; and inaddition where CH--CH or CH₂ --CH₂ bonds exist the level of unsaturationmay be increased,

and physiologically acceptable salts of any and/or all of the foregoing.

An illustrative of compound of particular interest in this class is,which hereinafter shall be referred to as: ##STR19##

J. As used herein and the appended claims the following molecule shallbe referred to as J-1 and said molecule represents the general class ofcompounds having the structure: ##STR20## wherein, R¹ is represented byone of the substituents of Group 2, and R² and R³, which may be the sameor different, may be represented by one of the substituents of Group 3,in any combination; and in addition where C═C bonds exist the level ofsaturation my be increased or decreased, and where CH--CH bonds existthe level of unsaturation my be increased,

and physiologically acceptable salts of any and/or all of the foregoing.

Illustrative of compounds of particular interest in this class are:

1. R³ =CH₃, R² =H, R¹ =isopropyl,

2. R³ =benzyl, R² =H, R¹ =H,

3. R¹ =R³ =H, R² =COOH,

4. R² =R³ =H, R² =p-cyanophenylcarbamoyl

and physiologically acceptable salts of any and/or all of the foregoing.

K. As used herein and the appended claims the following molecule shallbe referred to as K-1 and said molecule represents the general class ofcompounds having the structure: ##STR21## wherein p may be 1, 2, 3 or 4;the substituents R², which may be the same or different, are eachrepresented by one of the substituents of Group 1, in any combination,and R¹ is represented by one of the

substituents of Group 2, wherein R¹ and R² may be

present, in any combination,

and physiologically acceptable salts of any and/or all of the foregoing.

An illustrative of compound of particular interest in this class is:

1. R¹ =H, R² =benzyl, p=1,

2. R¹ =H, R² =NO₂, p=1,

3. R¹ =H, R² =CN, p=1,

4. R² =H, R¹ =cyanophenylcarbamoyl

and physiologically acceptable salts of any and/or all of the foregoing.

L. As used herein and the appended claims the following molecule shallbe referred to as L-1 and said molecule represents the general class ofcompounds having the structure: ##STR22## wherein R, R¹ and R², whichmay be the same or different, may each be represented by one of thesubstituents of Group 2; p may be 0 or 1; each R³ and R⁴ may beindependently represented by one of the substituents of Group 3; n maybe 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,or 20; Z is an element selected from the group consisting of carbon,sulfur, boron, or phosphorus; q is an integer from 2 to 3 and r is aninteger from 1 to 3, when Z is C, q is 2; when Z is S, P or B, q may be2 or 3; when Z is C or S, r is 1; when Z is P or B, r is 2; R¹ or R² canbe eliminated with OH to give a cyclic amide; and in addition whereCH--CH or CH₂ --CH₂ bonds exist the level of unsaturation may beincreased,

and physiologically acceptable salts of any and/or all of the foregoing.

Illustrative of compounds of particular interest in this class are:

1. R¹ =H, R² =t-butyl, Z=S, q=3, r=1, n=0, p=0,

2. R¹ =H, n=0, R² =1,2,3-trimethylcyclohexyl, Z=S, q=3, r=1,

3. R¹ =R² =R³ =R⁴ =H, n=2, Z=S, q=3, r=1 (This compound is also referredto as taurine.)

4. R¹ =R² =R³ =R⁴ =H, n=2, Z=C, q=2, r=1, p=0 (This compound is alsoreferred to as β-alanine.)

5. R¹ =p-cyanophenylcarbamoyl, R² =R³ =R⁴ =H, Z=C, q=2, r=1, n=1, p=0

6. R³ =R⁴ =R2=R¹ =H, n=2, Z=P, q=3, r=2, p=0

and physiologically acceptable salts of any and/or all of the foregoing.

M. As used herein and the appended claims the following molecule shallbe referred to as M-1 and said molecule represents the general class ofcompounds having the structure: ##STR23## wherein p may be 1, 2, 3 or 4,substituents R, R¹ and R², which may be the same or different, are eachindependently represented by one of the substituents of Group 1, in anycombination and R³ is represented by one of the substituents of Group 2,wherein R, R¹, R² and R³ may be present in any combination, and whereC═C or C═N bonds exist, the level of saturation may be decreased,

and physiologically acceptable salts of any and/or all of the foregoing.

An illustrative of compound of particular interest in this class is:

1. R¹ =R³ =phenyl, R² =H,

and physiologically acceptable salts of any and/or all of the foregoing.

N. As used herein and the appended claims the following molecule shallbe referred to as N-1 and said molecule represents the general class ofcompounds having the structure: ##STR24## wherein p may be 1, 2, 3, or4; q may be 1, 2, 3, 4, or 5; the substituents R¹ and R², which may bethe same or different are each independently represented by one of thesubstituents of Group 1, in any combination, the substituents R³ and R⁴,which may be the same or different are each represented by one of thesubstituents of Group 3, in any combination, r is 1 or 2; and inaddition where CH--CH or CH₂ --CH₂ bonds exist the level of unsaturationmay be increased,

and physiologically acceptable salts of any and/or all of the foregoing.

Illustrative of compounds of particular interest in this class is thefollowing molecules which as used herein and the appended claims shallbe referred to as N-2: ##STR25## and 5-hydroxyflavone (CAS 491-78-1).

O. The general class of compounds comprising amino acids and poly aminoacids.

This class includes but is not limited to:

1. naturally occurring α, β, γ, δ and/or

2. in general ω amino acids and/or

3. unnatural amino acids and/or

4. peptides and poly amino acids

The nitrogen atoms of these compounds may be substituted with one, twoor three substituents of Group 2, as appropriate. If oxygen (O) orsulfur (S) atoms exist in these molecules they may be substituted withan appropriate number of substituents from Group 2. Any aromatic groupsin these compounds may be substituted with one or more of thesubstituents of Group 1 in any combination,

and physiologically acceptable salts of any and/or all of the foregoing.

Illustrative of compounds of particular interest in this class are:

1. D-glutamic acid,

2. D-aspartic acid,

3. aminomalonic acid,

4. β-aminoethanesulfonic acid,

5. β-alanine,

6. 3,4-dihydroxyphenylalanine,

7. L-aspartyl-L-aspartic acid

and physiologically acceptable salts of any and/or all of the foregoing.

P. As used herein and the appended claims the following molecule shallbe referred to as P-1 and said molecule represents the general class ofcompounds having the generalized structure: ##STR26## One skilled in theart will recognize that this general structure (which would not likelyexist) is a representation of Several tautomers several of which arerepresented by the following: ##STR27## wherein the substituents R andR³, which may be the same or different, are each represented by one ofthe substituents of Group 1, in any combination; R¹ and R² which may bethe same or different, may-each be represented by one of thesubstituents of Group 2, in any combination, and A may be C, S, N, or Oand when A is C, substitution on this carbon may be made with one ormore of the substituents of Group 1, in any combination, when A is S orN substitution on this S or N may be made with one of the substituentsof Group 2, and where C═C or C═N bonds exist, the level of saturationmay be decreased,

and physiologically acceptable salts of any and/or all of the foregoing.

Illustrative of compounds of particular interest in this class are:

1. Xanthosine-5'-monophosphate

2. Inosine

3. Guanosine

and physiologically acceptable salts of any and/or all of the foregoing.

Q. As used herein and the appended claims the following molecule shallbe referred to as Q-1 and said molecule represents the general class ofcompounds having the generalized structure: ##STR28## One skilled in theart will recognize that this general structure (which would not likelyexist) is a representation of several tautomers several of which arerepresented by the following: ##STR29## wherein R₁, R₂, R₃, and R₅,which may be the same or different, are each represented by one of thesubstituents of Group 1, in any combination; R₄ and R₆, which may be thesame or different, are represented by one of the substituents of Group2, in any combination, and A may be C, S, N, or O and when A is C,substitution on this carbon may be made with one or more of thesubstituents of Group 1, in any combination, when A is S or Nsubstitution on this S or N may be made with one of the substituents ofGroup 2, and where C═C or C═N bonds exist, the level of saturation maybe decreased,

and physiologically acceptable salts of any and/or all of the foregoing.

It will be recognized by one skilled in the art that this class isintended to include any oxidation state of the ring system, as forexample, hydrogenation of one or more of the double bonds.

Illustrative of compounds of particular interest in this class are:

1. Orotic Acid

2. Dihydroorotic acid

and physiologically acceptable salts of any and/or all of the foregoing.

R. The class of compounds commonly known as natural products. This classincludes but is not limited to:

alkaloids, terpines, monoterpines, diterpines, triterpines,sesqueterpines, flavanoides, chalcones, dihydrochalcones, humulones,lemonoids, saponhins, coumarins, isocoumarins, sinapines, steroids,flavinones,

and physiologically acceptable salts of any and/or all of the foregoing.

As used herein and the appended claims the following molecule shall bereferred to as R-1, and said molecule exemplifies the general class ofcompounds having, but not limited to the following structure: ##STR30##and physiologically acceptable salts of any and/or all of the foregoing.

As used herein and the appended claims the following molecule shall bereferred to as R-2 and said molecule represents the general class ofcompounds having, but not limited to the following structure: ##STR31##and physiologically acceptable salts of any and/or all of the foregoing.

As used herein and the appended claims the following molecule shall bereferred to as R-3 and said molecule represents the general class ofcompounds having, but not limited to the following structure: ##STR32##and physiologically acceptable salts of any and/or all of the foregoing.

As used herein and the appended claims the following molecule shall bereferred to as R-4 and said molecule represents the general class ofcompounds having, but not limited to the following structure: ##STR33##and physiologically acceptable salts of any and/or all of the foregoing.

As used herein and the appended claims the following molecule shall bereferred to as R-5 and said molecule represents the general class ofcompounds having; but not limited to the following structure: ##STR34##and physiologically acceptable salts of any and/or all of the foregoing.

As used herein and the appended claims the following molecule shall bereferred to as R-6 and said molecule represents the general class ofcompounds having, but not limited to the following structure: ##STR35##and physiologically acceptable salts of any and/or all of the foregoing.

As used herein and the appended claims the following molecule shall bereferred to as R-7 and said molecule represents the general class ofcompounds having, but not limited to the following structure: ##STR36##and physiologically acceptable salts of any and/or all of the foregoing.

As used herein and the appended claims the following molecule shall bereferred to as R-8 and said molecule represents the general class ofcompounds having, but not limited to the following structure: ##STR37##and physiologically acceptable salts of any and/or all of the foregoing.

As used herein and the appended claims the following molecule shall bereferred to as R-9 and said molecule represents the general class ofcompounds having, but not limited to the following structure: ##STR38##and physiologically acceptable salts of any and/or all of the foregoing.

As used herein and the appended claims the following molecule shall bereferred to as R-10 and said molecule represents the general class ofcompounds having, but not limited to the following structure: ##STR39##and physiologically acceptable salts of any and/or all of the foregoing.

As used herein and the appended claims the following molecule shall bereferred to as R-11 and said molecule represents the general class ofcompounds having, but not limited to the following structure: ##STR40##and physiologically acceptable salts of any and/or all of the foregoing.

As used herein and the appended claims the following molecule shall bereferred to as R-12 and said molecule represents the general class ofcompounds having, but not limited to the following structure: ##STR41##and physiologically acceptable salts of any and/or all of the foregoing.

As used herein and the appended claims the following molecule shall bereferred to as R-13 and said molecule represents the general class ofcompounds having, but not limited to the following structure: ##STR42##and physiologically acceptable salts of any and/or all of the foregoing.

As used herein and the appended claims the following molecule shall bereferred to as R-14 and said molecule represents the general class ofcompounds having, but not limited to the following structure: ##STR43##and physiologically acceptable salts of any and/or all of the foregoing.

As used herein and the appended claims the following molecule shall bereferred to as R-15 and said molecule represents the general class ofcompounds having, but not limited to the following structure: ##STR44##and physiologically acceptable salts of any and/or all of the foregoing.

As used herein and the appended claims the following molecule shall bereferred to as R-16 and said molecule represents the general class ofcompounds having, but not limited to the following structure: ##STR45##and physiologically acceptable salts of any and/or all of the foregoing.

As used herein and the appended claims the following molecule shall bereferred to as R-17 and said molecule represents the general class ofcompounds having, but not limited to the following structure: ##STR46##and physiologically acceptable salts of any and/or all of the foregoing.

As used herein and the appended claims the following molecule shall bereferred to as R-18 and said molecule represents the general class ofcompounds having, but not limited to the following structure: ##STR47##and physiologically acceptable salts of any and/or all of the foregoing.

As used herein and the appended claims the following molecule shall bereferred to as R-19 and said molecule represents the general class ofcompounds having, but not limited to the following structure: ##STR48##and physiologically acceptable salts of any and/or all of the foregoing.

As used herein and the appended claims the following molecule shall bereferred to as R-20 and said molecule represents the general class ofcompounds having, but not limited to the following structure: ##STR49##and physiologically acceptable salts of any and/or all of the foregoing.

As used herein and the appended claims the following molecule shall bereferred to as R-21 and said molecule represents the general class ofcompounds having, but not limited to the following structure: ##STR50##and physiologically acceptable salts of any and/or all of the foregoing.

As used herein and the appended claims the following molecule shall bereferred to as R-22 and said molecule represents the general class ofcompounds having, but not limited to the following structure: ##STR51##and physiologically acceptable salts of any and/or all of the foregoing.

As used herein and the appended claims the following molecule shall bereferred to as R-23 and said molecule represents the general class ofcompounds having, but not limited to the following structure: ##STR52##and physiologically acceptable salts of any and/or all of the foregoing.

As used herein and the appended claims the following molecule shall bereferred to as R-24 and said molecule represents the general class ofcompounds having, but not limited to the following structure: ##STR53##and physiologically acceptable salts of any and/or all of the foregoing.

As used herein and the appended claims the following molecule shall bereferred to as R-25 and said molecule represents the general class ofcompounds having, but not limited to the following structure: ##STR54##and physiologically acceptable salts of any and/or all of the foregoing.

As used herein and the appended claims the following molecule shall bereferred to as R-26 and said molecule represents the general class ofcompounds having, but not limited to the following structure: ##STR55##and physiologically acceptable salts of any and/or all of the foregoing.

As used herein and the appended claims the following molecule shall bereferred to as R-27 and said molecule represents the general class ofcompounds having, but not limited to the following structure: ##STR56##and physiologically acceptable salts of any and/or all of the foregoing.

As used herein and the appended claims the following molecule shall bereferred to as R-28 and said molecule represents the general class ofcompounds having, but not limited to the following structure: ##STR57##and physiologically acceptable salts of any and/or all of the foregoing.

As used herein and the appended claims the following molecule shall bereferred to as R-29 and said molecule represents the general class ofcompounds having, but not limited to the following structure: ##STR58##and physiologically acceptable salts of any and/or all of the foregoing.

As used herein and the appended claims the following molecule shall bereferred to as R-30 and said molecule represents the general class ofcompounds having, but not limited to the following structure: ##STR59##and physiologically acceptable salts of any and/or all of the foregoing.

As used herein and the appended claims the following molecule shall bereferred to as R-31 and said molecule represents the general class ofcompounds having, but not limited to the following structure: ##STR60##and physiologically acceptable salts of any and/or all of the foregoing.

As used herein and the appended claims the following molecule shall bereferred to as R-32 and said molecule represents the general class ofcompounds having, but not limited to the following structure: ##STR61##and physiologically acceptable salts of any and/or all of the foregoing.

As used herein and the appended claims the following molecule shall bereferred to as R-33 and said molecule represents the general class ofcompounds having, but not limited to the following structure: ##STR62##and physiologically acceptable salts of any and/or all of the foregoing.

As used herein and the appended claims the following molecule shall bereferred to as R-34 and said molecule represents the general class ofcompounds having,-but not limited to the following structure: ##STR63##and physiologically acceptable salts of any and/or all of the foregoing.

As used herein and the appended claims the following molecule shall bereferred to as R-35 and said molecule represents the general class ofcompounds having, but not limited to the following structure: ##STR64##and physiologically acceptable salts of any and/or all of the foregoing.

As used herein and the appended claims the following molecule shall bereferred to as R-36 and said molecule represents the general class ofcompounds having, but not limited to the following structure: ##STR65##and physiologically acceptable salts of any and/or all of the foregoing.

The above examples and other natural products of this class may betransformed (as per the usage of this term defined above) to additionaltastands by a variety of chemical modifications. Thus, we envisageadditional tastands in which the above examples can be modified byvariation of the valency or oxidation state of any carbon atom, in whichepoxides may be opened by oxidation or nucleophilic substitution or maybe reduced to alcohols, in which lactones may be converted to hydroxyacids or hydroxy acids may be cyclized to lactones, or in which enoltautomers are converted to the appropriate keto tautomer. Furthermore,the ring systems depicted in the above examples may be substituted witha variety of aliphatic, alicyclic, aromatic groups, hydroxy, amino, orother substituents of group 1 or 3, as defined above, and hydroxyl,amino or thio groups may be substituted with one of the substituents ofgroup 2, as defined above. The stereochemical relationships of thesubstituents may be cis or trans, and chiral centers may be of R or Sconfiguration. In all examples nitrogen or oxygen atoms may besubstituted with group 2, substituents or mono or polysaccharidesincluding but not restricted to those indicated in the above examples.

Illustrative of compounds of particular interest in this class are thefollowing:

As used herein and the appended claims the following molecules shall bereferred to as R-37: ##STR66## where: 1. R₁ =β-D-glc, R₂ =α-L-rha-3-Me,

2. R₁ =β-D-glc² -α-L-rha, R₂ =H

and physiologically acceptable salts of any and/or all of the foregoing.

As used herein and the appended claims the following molecule shall bereferred to as R-38: ##STR67## and physiologically acceptable salts ofany and/or all of the foregoing.

As used herein and the appended claims the following molecules shall bereferred to as R-39: ##STR68## and physiologically acceptable salts ofany and/or all of the foregoing.

As used herein and the appended claims the following molecules shall bereferred to as R-40: ##STR69## and physiologically acceptable salts ofany and/or all of the foregoing.

As used herein and the appended claims the following molecules shall bereferred to as R-41: ##STR70## and physiologically acceptable salts ofany and/or a of the foregoing.

As used herein and the appended claims the following molecule shall bereferred to as R-42: ##STR71## and physiologically acceptable salts ofany and/or all of the foregoing.

As used herein and the appended claims the following molecule shall bereferred to as R-43: ##STR72## and physiologically acceptable salts ofany and/or all of the foregoing.

As used herein and the appended claims the following molecule shall bereferred to as R-44: ##STR73## and physiologically acceptable salts ofany and/or all of the foregoing.

As used herein and the appended claims the following molecule shall bereferred to as R-45: ##STR74## and physiologically acceptable salts ofany and/or all of the foregoing.

As used herein and the appended claims the following molecule shall bereferred to as R-46: ##STR75## and physiologically acceptable salts ofany and/or all of the foregoing.

As used herein and the appended claims the following molecules shall bereferred to as R-47: ##STR76## and physiologically acceptable salts ofany and/or all of the foregoing.

As used herein and the appended claims the following molecule shall bereferred to as R-48: ##STR77## and physiologically acceptable salts ofany and/or all of the foregoing.

As used herein and the appended claims the following molecule shall bereferred to as R-49: ##STR78## and physiologically acceptable salts ofany and/or all of the foregoing.

As used herein and the appended claims the following molecule shall bereferred to as R-50: ##STR79## and physiologically acceptable salts ofany and/or all. of the foregoing.

As used herein and the appended claims the following molecule shall bereferred to as R-51: ##STR80## and physiologically acceptable salts ofany and/or all of the foregoing.

As used herein and the appended claims the following molecules shall bereferred to as R-52: ##STR81## and physiologically acceptable salts ofany and/or all of the foregoing.

As used herein and the appended claims the following molecule shall bereferred to as R-53: ##STR82## and physiologically acceptable salts ofany and/or al of the foregoing.

As used herein and the appended claims the following molecule shall bereferred to as R-54: ##STR83## and physiologically acceptable salts ofany and/or all of the foregoing.

As used herein and the appended claims the following molecules shall bereferred to as R-55: ##STR84## and physiologically acceptable salts ofany and/or all. of the foregoing.

S. The class of compounds having the structure, or structures closelyrelated to the following molecule which as used herein and the appendedclaims shall be referred to as S-1: ##STR85## wherein R₁, R₂, R₃, and R₄which may be the same or different are each designated by one of thesubstituents of Group 1. R₅ is represented by one of the substituents ofGroup 2, and R₆ is represented by one of the substituents of Group 3,wherein R₁, R₂, R₃, R₄, R₅, and R₆, may be present in any combination;and in addition where C═C bonds exist the level of saturation may bedecreased, and where CH--CH bonds exist the level of unsaturation my beincreased,

and physiologically acceptable salts of any and/or all of the foregoing.

Of particular interest is the compound having the structure (commonlyknown as epihernandulcin): ##STR86##

T. The class of compounds having the structure (or structures closelyrelated to) which as used herein and the appended claims shall bereferred to as T-1: ##STR87## wherein p may be 1, 2, 3, 4 or 5; R¹,which may be the same or different, are each represented by one of thesubstituents of Group 1 in any combination; R² and R³, which may be thesame or different, are each represented by one of the substituents ofGroup 2; each R⁴ and R⁵ may be independently represented by one of thesubstituents of Group 3 and wherein R¹, R² R³ R⁴, and R⁵ may be presentin any combination; n may be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, or 20; Z may be an element selected from thegroup consisting of carbon, sulfur, boron, or phosphorus; q is aninteger from 2 to 3 and r is an integer from 1 to 3, when Z is C, q is2; when Z is S, P or B, q may be 2 or 3; when Z is C or S, r is 1; whenZ is P or B, r is 2; and in addition where CH--CH or CH₂ --CH₂ bondsexist the level of unsaturation may be increased,

and physiologically acceptable salts of any and/or all of the foregoing.

Illustrative of compounds of particular interest in this class are:

1. R² =R³ =R⁴ =R⁵ =H, n=2, R¹ =p-cyano, Z=C, q=2 r=1, p=1

2. R² =R³ =R⁴ =R⁵ =H, n=2, R¹ =p-nitro, Z=C, q=2, r=1, p=1

3. R¹ =p-cyano; R² =R³ =R⁴ =R⁵ =H, n=1, Z=P, q=3, r=2, p=1

4. R¹ =p-nitro; R² =R³ =R⁴ =R⁵ =H, n=1, Z=P, q=3, r=2, p=1

5. R¹ =p-cyano; R² =R³ =R⁴ =R⁵ =H, n=1, Z=S, q=3, r=1, p=1

6. R¹ =p-nitro; R² =R³ =R⁴ =R⁵ =H, n=1, Z=S, q=3, r=1, p=1

and physiologically acceptable salts of any and/or all of the foregoing.

U. The class of compounds having the structure (or structures closelyrelated to) which as used herein and the appended claims shall bereferred to as U-1: ##STR88## wherein A may be O(oxygen), S(sulfur), orC(carbon), and when A is C, n is 1 and when A may be O or S, n is zero;R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹², which may be thesame or different, and which may be present in any combination, may eachbe represented by one of the following: one of the substituents of"Group 1", O--R¹³, NH-R¹³, N-(R¹³)₂, or S--R¹³, where R¹³ is representedby one of the substituents of "Group 2"; or two R substituents may bedehydrated to form an anhydride linkage; or two R substituents may forma cyclic structure; and in addition where CH--CH or CH₂ --CH₂ bondsexist the level of unsaturation may be increased,

and physiologically acceptable salts of any and/or all of the foregoing.

One skilled in the art would recognize the six membered (pyranose) ringsof this class may isomerize to five membered (furanose) rings as is wellknown for many sugars.

Illustrative of compounds of particular interest in this class are:

1. 6-chloro-6-deoxytrehalose,

2. 6',6-dichloro-6',6-dideoxytrehalose,

3. 6-chloro-6-deoxy-D-galactose,

4. 6-chloro-6-deoxy-D-mannose,

5. 6-chloro-6-deoxy-D-mannitol,

6. methyl-2,3-di-(glycyl-glycyl)-α-D-glucopyanoside,

7. methyl-2-O-methyl-α-D-glucopyranoside,

8. methyl-3-O-methyl-α-D-glucopyranoside,

9. methyl-4-O-methyl-α-D-glucopyranoside,

10. methyl-6-O-methyl-α-D-glucopyranoside,

11. 2,2'-di-O-methyl-α,α-trehalose,

12. 3,3'-di-O-methyl-α,α-trehalose,

13. 4,4'-di-O-methyl-α,α-trehalose,

14. 6,6'-di-O-methyl-α,α-trehalose,

15. 6'-O-methylsucrose,

16. 4'-O-methylsucrose,

17. 6,6'-di-O-methylsucrose,

18. 4,6'-di-O-methylsucrose,

19. 1,6'-di-O-methylsucrose,

20. cyclohexane 1,2/4,5 tetrol,

21. (+)-cyclohexane 1,3,4/2,5 pentol[(+)-proto quercitol],

22. (-)-cyclohexane 1,3,4/3,5 pentol[(-)-vibo quercitol],

23. cyclohexane 1,2,3/4,5,6 hexol [neo Inositol],

24. cyclohexane 1,2,3,5/4,6 hexol [myo Inositol],

25. cyclohexane 1,2,4,5/3,6 hexol [muco Inositol],

26. methyl-α-D-arabinopyranoside,

27. methyl-3-deoxy-α-D-arabinohexopyranoside,

28. 3-deoxy-α-D-arabinohexopyranosyl-3-deoxy-α-D-arabinohexopyranose,

29. 2-deoxy-α-D-ribo-hexopyranosyl-2-deoxy-α-D-ribohexopyranose,

30. 3-deoxy-α-D-ribo-hexopyranosyl-3-deoxy-α-D-ribohexopyranose,

31. 1,6-anhydro-3-dimethylamino-3-deoxy-β-D-glucopyranose,

32. 1,6-anhydro-3-dimethylamino-3-deoxy-β-D-altropyranose,

33. 1,6-anhydro-3-acetamido-3-deoxy-β-D-glucopyranose,

34. 1,6-anhydro-3-acetamido-3-deoxy-α-D-gulopyranose,

35. 1,6-anhydro-3-amino-3-deoxy-β-D-gulopyranose,

36. methyl-3,6-anhydro-α-D-glucopyranoside,

37. 3,6-anhydro-α-D-glucopyransyl-3,6-anhydro-α-D-glucopyranoside,

38. 3,6-anhydro-α-D-glucopyransyl-3,6-anhydro-α-D-fructofuranoside

39.3,6-anhydro-α-D-glucopyransyl-1,4:3,6-dianhydro-β-D-fructofuranoside,

and physiologically acceptable salts of any and/or all of the foregoing.

V. The class of compounds having the structure (or structures closelyrelated to) which as used herein and the appended claims shall bereferred to as V-1: ##STR89## wherein a, r, l, and m may be 0 or 1; n,j, and k are 0, 1, 2, or 3; each R² and R³ which may be the same ordifferent independently may each be represented by one of thesubstituents of group 3; Y (which may be the same or different) may be N(nitrogen), O (oxygen), c,r S (sulfur); when r or m is 1 and Y is N, por q may be 2 or 3, when r or m is 1 and Y is 0, p or q is 1; when r orm is 1 and Y is S, p may be 1 or 2; A may be H, C═O, O═S═O, S═O,O═P(H)OH, O═P(OH)₂, or O═B(H)OH; Q is represented by one of thesubstituents of Group 3; R (which may be the same or different when p>1)and R' (which may be the same or different when q>1) are represented byone of the substituents of Group 2 or one of the following threestructures (as used herein and the appended claims the structures shallbe referred to as V-2) in any combination and the appropriatestereochemistry: ##STR90## wherein Y (which may be the same ordifferent) may be N (nitrogen), O (oxygen), or S (sulfur); when d is 1and b is 0 and Y is N, e may be 2 or 3, when d is 1 and b is 0 and Y isO, e is 1; f may be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10; when d is 1 and bis 0 and Y is S, e may be 1 or 2; A may be H, C═O, O═S═O, S═O, O═P(H)OHor O═P(OH)₂, O═B(H)OH; Q is represented by one of the substituents ofGroup 3; R'" and Q together may form a cyclic structure; any of the R³'s and Q together may form a cyclic structure; any of the R³ 's andR'"'s together may form a cyclic structure; b may be 0, 1, or 2 and cmay be 0 or 1; Z and Z' are the same or different and are represented byOH, --O⁻ X⁺, OR", NH₂, NHR", N(R")_(2') ; R" may be alkyl, branchedalkyl, aryl, aralkyl, alkaryl, cycloalkyl, substituted alkyl,substituted cycloalkyl substituted aryl, substituted aralkyl,substituted alkaryl, and R'" may be alkyl, branched alkyl, aryl,aralkyl, alkaryl, cycloalkyl, substituted alkyl, substituted cycloalkyl,substituted aryl, substituted aralkyl, substituted alkaryl, or an aminoacid side chain (e.g. one of the 20 common amino acids); and in additionwhere CH--CH or CH₂ --CH₂ bonds exist the level of unsaturation may beincreased. X⁺ may be H⁺ or a physiologically acceptable cation,preferably an alkali metal, alkaline earth metal or ammonium cation,

and physiologically acceptable salts of any and/or all of the foregoing.

Illustrative of compounds of particular interest in this class are:

1. N-(L-aspartyl)-p-aminobenzenesulfonic acid,

2. N-(aminomalonyl)-p-aminobenzenesulfonic acid,

3. amino ethane phosphoric acid,

4. N-[N-(p-cyanophenylcarbamoyl)-L-aspartyl]-p-aminobenzenesulfonicacid,

5. N(-L-aspartyl)-1-aminocyclopentane-1-carboxylic acid,

6. N(-L-aspartyl)-1-aminocyclopropane-1-carboxylic acid,

7. N(-L-aspartyl)-1-aminocyclooctane-1-carboxylic acid,

8. N(-L-aspartyl)-1-aminocyclohexane-1-carboxylic acid,

9. N(-L-aspartyl)-2-aminocyclopentane-1-carboxylic acid,

and physiologically acceptable salts of any and/or all of the foregoing.

W. The class of compounds having the structure (or structures closelyrelated to) which as used herein and the appended claims shall bereferred to as W-1: ##STR91## wherein r, l, and m may be 0 or 1; j, andk may be 0, 1, 2, or 3; each R² and R³ which may be the same ordifferent independently may each be represented by one of thesubstituents of group 3; Y (which may be the same or different) may be N(nitrogen), O (oxygen), or S (sulfur); when r or m is 1 and Y is N, p orq may be 2 or 3, when r or m is 1 and Y is O, p or q is 1; when r or mis 1 and Y is S, p may be 1 or 2; A may be H, C═O, O═S═O, S═O, O═P(H)OH,O═P(OH)₂, or O═B(H)OH; Q is represented by one of the substituents ofGroup 3; R"" and Q together may form a cyclic structure; any of the R³'s and Q together may form a cyclic structure; any of the R³ 's and R'"together may form a cyclic structure; R (which may be the same ordifferent when p>1) and R' (which may be the same or different when q>1)are represented by one of the substituents of Group 2 or one of thefollowing three structures (as used herein and the appended claims thestructures shall be referred to as W-2) in any combination and theappropriate stereochemistry: ##STR92## wherein Y (which may be the sameor different) may be N (nitrogen), O (oxygen), or S (sulfur); when d is1 and b is 0 and Y is N, e may be 2 or 3, when d is 1 and b is 0 and Yis O, e is 1; f may be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10; when d is 1 andb is 0 and Y is S, e may be 1 or 2; A may be H, C═O, O═S═O, S═O,O═P(H)OH or O═P(OH)₂, O═B(H)OH; Q is represented by one of thesubstituents of Group 3; b may be 0, 1, or 2 and c may be 0 or 1; Z andZ' are the same or different and are represented by OH, --O⁻ X⁺, OR",NH₂, NHR", N(R")_(2') ; R" may be alkyl, branched alkyl, aryl, aralkyl,alkaryl, cycloalkyl, substituted alkyl, substituted cycloalkylsubstituted aryl, substituted aralkyl, substituted alkaryl, and R'" maybe alkyl, branched alkyl, aryl, aralkyl, alkaryl, cycloalkyl,substituted alkyl, substituted cycloalkyl, substituted aryl, substitutedaralkyl, substituted alkaryl, or an amino acid side chain (e.g. one ofthe 20 common amino acids); and in addition where CH--CH or CH₂ --CH₂bonds exist the level of unsaturation may be increased. X⁺ may be H⁺ ora physiologically acceptable cation, preferably an alkali metal,alkaline earth metal or ammonium cation, and physiologically acceptablesalts of any and/or all of the foregoing.

Illustrative of compounds of particular interest in this class are:

1. L-ornithyl-taurine

2. L-ornithyl-β-alanine

3. L-lysyl-taurine

4. L-diaminobutyryl-taurine

5. L-diaminobutyryl-β-alanine

6. L-diaminopropionyl-β-alanine

7. L-diaminopropionyl-taurine

8. L-lysyl-β-alanine

9. L-methionyl-taurine

10. L-methionyl-β-alanine

11. N-(L-ornithyl-)-p-aminobenzenesulfonic acid

and physiologically acceptable salts of any and/or all of the foregoing.

X. The general class of compounds commonly referred to as chelators.These are molecules capable of chelating with, binding with, complexingwith or coordinating with metal ions. Included in this class are thephysiologically acceptable salts of any and/or all of the foregoing.

Illustrative of compounds of particular interest in this class are:

1. Ethylenediaminetetraacetic acid (EDTA) and physiologically acceptablesalts thereof.

2. Tartaric acid and physiologically acceptable salts thereof.

3. Lactic acid and physiologically acceptable salts thereof.

4. Ascorbic acid and physiologically acceptable salts thereof.

It should be understood that the present invention contemplates the useof chelating agents that have varying degrees of affinity for metal ionsrelative to the above listed compounds. Many of these more or lesseffective compounds are listed in A through W hereinabove. A fewillustrative examples are:

1. 2,4-Dihydroxybenzoic acid,

2. 3,4-Dihydroxybenzoic acid,

3. α-Amino acids,

4. α-Hydroxy acids,

5. peptides,

6. sulfonamides,

7. β-Amino acids,

and physiologically acceptable salts thereof.

Y. Tastand Enhancers: The effectiveness of any individual tastand asdescribed in Classes A-X may be enhanced by one surfactant while thesame surfactant may lessen the effectiveness of other tastands or notaffect that particular tastand at all.

Illustrative examples of surfactants:

1. tergitols

2. pluronics

3. poloxamars

4. quaternary ammonium salts

5. sorbitans

6. tritons

7. polyoxyethene ethers

8. sulfonic acid salts

Surfactants can increase the effectiveness of some tastands while thesame surfactant may lessen the effectiveness of other tastands or notaffect that particular tastand at all. Surfactants may affect eachtastand differently. The surfactant that affects one particular tastandin a positive, negative or neutral sense may affect another tastanddifferently (i.e. a positive, negative or neutral sense and notnecessarily in the same way).

Z. Tastand Model: In 1967, Shallenberger and Acree (Nature (London)1967, 216, 480-482; which is hereby incorporated by reference) proposedthat all compounds that elicit a sweet taste response possess an AH, Bsystem (AH being a hydrogen bond donor and B being a hydrogen bondacceptor) separated by about 0.28 to 0.40 nm. In this theory, AH was OHor NH and B an oxygen atom in groups such as CO₂ H, SO₂ H, SO₂, CO, NO₂,the nitrogen atom of CN, or even a halogen. For instance, inL-aspartyl-L-phenylalanine methyl ester the NH₃ ⁺ is the AH and the COO⁻is the B. They suggested that such compounds interacted with a sweetreceptor by a pair of reciprocal hydrogen bonds (a complementary AH, Bsystem). This theory was widely accepted by most of the researchers inthe field.

In 1972, Kier (J. Pharm. Sci. 1972, 61, 1394; which is herebyincorporated by reference) expanded on the model of Shallenberger andAcree and proposed the existence of a third binding site which involveda hydrophobic interaction, which he designated as X. A molecule whichwould interact with all three (AH, B, and X) would be a higher potencysweetener than one which only interacted with the AH, B site. Ariyoshi(Bull. Chem. Soc. Japan, 1974, 47, 326-330; which is hereby incorporatedby reference) and van der Heijden (Feed Chem. 1978, 3,207; which ishereby incorporated by reference) added configurational restraints forthe X group, that resulted in assigning a 5.5 nm spacing for the B and Xsites and a 3.5 nm separation for the AH and X sites. This model hasbecome widely accepted and has been studied extensively by a number ofresearchers including Goodman and co-workers, Temussi and co-workers,Tinti and Nofre and co-workers, and Belitz who has also studied therequirements for bitter response in his modeling systems.

Goodman (Sweeteners, ACS Symposium Series 450, Chapt. 10, 128-142; whichis hereby incorporated by reference) has further refined therequirements necessary for a molecule to elicit a sweet response bydeveloping three dimensional requirements for the AH, B, X system. Tintiand Nofre (Sweeteners, ACS Symposium Series 450, Chapter 7 and 15; whichare hereby incorporated by reference) have identified a fourth primarybinding site which they call "D" (they refer to the "X" site as "G") andfour secondary binding sites (FIG. 1). The D site in a sweetener is ahydrogen bond accepter group and appears to be particularly effectivewhen this group is a --CN or a --NO₂ group. Using this 8 centered model,they have developed extremely potent sweeteners which interact with allfour primary sites and several secondary sites.

Goodman (J. Am. Chem. Soc. 1987, 101, 4712-4714; which is herebyincorporated by reference) reports that the four stereoisomerictetramethylcyclopentane compounds;L-aspartyl-L-alanyl-2,2,5,5-tetramethylcyclopentyl amide,L-aspartyl-D-alanyl-2,2,5,5-tetramethylcyclopentyl amide,N-(L-aspartyl)-N'-(tetramethylcyclopentanoyl)-(S)-1,1-diaminoethane andN-(L-aspartyl)-N'-(2,2,5,5-tetramethylcyclopentanoyl)-(R)-1,1-diaminoethane,present a unique opportunity to study structure-taste relationships.Small changes in the overall topology affect the taste of these analogs(the L,L amide is bitter while the L,D amide and the retro-inversoanalogs are intensely sweet). In addition, the bulkytetramethylcyclopentane group greatly decreases the conformationalmobility of the peptide, allowing for a more complete analysis by NMR.With the assumption of a trans peptide bond and a nearly planarzwitterionic ring for the aspartyl moiety, the structure of thecompounds can be determined from an extensive conformational analysis byNMR. The coupling constants, NOE values, and temperature coefficientsused in defining the conformations of the four molecules were reported.The preferred minimum energy conformations are shown in FIG. 2. Based onthe results of this conformational study, Goodman proposed a model forsweet tasting analogs which contains elements of the models proposed byKier, Temussi, van der Heijden, Tinti and Nofre, and Shallenberger andAcree. The conformation of a sweet molecule can be described aspossessing an "L shape", with the A-H and B zwitterionic ring of theaspartyl moiety forming the stem, and the hydrophobic X (G in theTinti-Nofre model) group forming the base of the L (FIG. 3). Planarityof the molecule in the x and y dimensions is critical for sweet taste,substantial deviation from this plane into the z dimension is correlatedwith tasteless (+z) or bitter (-z) molecules. The existence of theaspartyl zwitterionic ring cannot be proven conclusively but can beassumed a priori on the basis of evidence obtained from NMR experiments.The Cα-Cβ bond of the aspartyl residue possesses a staggeredconformation with the carboxyl moiety and the amino group in the gaucheposition and the sp² plane of the terminal aspartyl carboxylate carbonatom and the Cα-Cβ bond coplanar. These conditions are conformationallyfavorable for the formation of the zwitterionic aspartyl ring.

The X-ray structure of L-aspartyl-L-phenylalanine methyl ester has beensolved by Kim (J. Am. Chem. Soc. 1985, 107, 4279; which is herebyincorporated by reference). Crystallization was achieved in thetetragonal space group P4₁ with four L-aspartyl-L-phenylalanine methylester molecules and one water molecule per unit cell. The molecule showsan extended conformation with trans peptide bonds. However, the phenylring is perpendicular to the peptide backbone and not coplanar with thezwitterionic ring of aspartic acid as would be predicted for a sweetdipeptide. This twisting of the phenyl ring is due to packing forceswithin the crystal structure which result in stacking of adjacentL-aspartyl-L-phenylalanine methyl ester molecules into stable columnarstructures. The isolated molecule from the crystal structure can berotated 40° about the φ.sub.(Phe) bond, to achieve an isoenergeticconformation in which the rings are coplanar. This conformationcorrelates closely to our proposed model for the structure of sweetdipeptides in solution (FIG. 3). Of course, in solution theL-aspartyl-L-phenylalanine methyl ester molecule is solvated and devoidof packing forces. Thus, the inherent flexibility of this linear peptidewill easily accommodate the "L-shape" conformation required by themodel. FIG. 4 depicts L-aspartyl-L-phenylalanine methyl ester in the L"shape" required for sweet taste in the Goodman model superimposed inthe 8-centered Tinti and Nofre model. In this configuration the NH₃ ⁺,COO⁻, and phenyl ring fit well into the AH, B and G sites required for asweet taste in the Tinti and Nofre model as well as the AH, B and Xsites of the Goodman model.

Belitz (ACS, Food Taste Chemistry, 1979, 93-131; which is herebyincorporated by reference) describes minimum requirements for bittertaste perception as a molecule possessing an AH group and a hydrophobicmoiety. Using the model ascribed to Goodman above the hydrophobic moietyof Belitz would be in the -z (or bitter taste) region described byGoodman.

It is a plausible consequence of the above models that molecules capableof binding to one or more of the taste receptor "sites" as described bythese researchers, and their models, and which do not allow ahydrophobic group into the "X" (or G, sweet taste) region or into the(-z) (bitter taste) area, is likely to be tasteless (or nearlytasteless). Such a molecule (a tastand as described herein above) wouldbe predicted to competitively bind to the receptor and cause inhibitionof one or more of the tastes (sweet, bitter, organic bitter) produced bysuch a receptor.

What we have found is that if a molecule is bitter or sweet andinteracts with the receptor site as described by the above models andsuch a molecule can be transformed in such a manner as to displace thehydrophobic portion of the molecule from the X (G, sweet taste) zone,and in such a manner that the hydrophobic portion does not interact withthe bitter taste (-z) zone, that such a molecule will tend to betasteless. Furthermore, the transformation of the hydrophobic zonesubstituent to a hydrophilic substituent, and/or the increasing ordecreasing of the size of the hydrophobic substituent, and/or theincreasing or decreasing of the distance between the various hydrogenbonding and hydrophobic interaction sites, may result in a change inbinding conformation and/or structure in a manner which preventssubstantial interaction with the sweet taste (G or X) zone orsubstantial interaction with the bitter taste (-z) zone, thus,generating a substantially tasteless molecule.

We have found that an inhibitor of sweet taste or bitter taste mayinteract in various ways with the receptor site. Consequently, dependingon the nature of the interaction of a tastand with the receptor, saidtastand may be capable of competing favorably against one class ofcompounds, say for instance sweeteners, and unfavorably against otherclasses of compounds such as bitter compounds.

Another consequence of our finding is that a model explaining both sweetand bitter taste might include the possibility that there are separatereceptors or receptor sites for sweet and bitter taste perception. Thus,if a tastand were to interact with only one of these receptors orreceptor sites it could completely eliminate one sensation withoutaffecting the other.

It has also been reported and we have found that there are at least twotypes of bitter taste. One is organic bitter taste which is elicited bycompounds such as caffeine and the other is the bitter taste elicited byinorganic molecules like potassium ion. Consequently, a tastand maycompete favorable against organic bitter taste, perhaps even favorablyagainst sweet taste as well, and unfavorably against potassium ion,depending on the sites of interaction. Conversely the tastand maycompete favorably against potassium ion and unfavorably against organicbitter or sweet tastes.

As an example of the transformations which are capable of eliciting theresponses just described, L-aspartyl-L-phenylalanine methyl ester isapproximately 200 times sweeter than sucrose. L-Aspartyl-L-phenylalaninemethyl ester can be transformed to a bitter compound by changing theL-phenylalanine methyl ester to D-phenylalanine methyl ester (whichplaces the phenyl ring in the -z (bitter taste) zone.L-Aspartyl-L-phenylalanine methyl ester can also be transformed to atasteless compound by changing the methyl ester to a carboxylic acid.L-Aspartyl-L-phenylalanine (L-aspartyl-L-phenylalanine methyl esterminus the methyl ester) is tasteless and has been shown to effectivelyblock the bitter taste of potassium ion. L-Aspartyl-L-phenylalanine hasminimal effect on the sweet taste of L-aspartyl-L-phenylalanine methylester but does block the sweet taste of sucrose at very highconcentrations (relative to the sucrose). L-Aspartyl-L-phenylalanine hasvery little effect on the bitter taste of caffeine but does block theoff-taste associated with L-aspartyl-L-phenylalanine methyl ester.N-(p-Cyanophenylcarbamoyl)-L-aspartyl-L-phenylalanine methyl ester asdescribed by Tinti and Nofre is 14,000 times sweeter than sucrose. Whenthis compound is transformed intoN-(p-cyanophenylcarbamoyl)-L-aspartyl-L-phenylalanine, i.e. the supersweetener minus the methyl ester, the compound becomes essentiallytasteless. This compound can now interact with the AH, B and D, but notwith the X(G), portions of the receptor site and we have found that thiscompound effectively blocks the bitter taste of potassium ion and thebitter taste of caffeine while having only a very small effect on thesweet taste of sucrose. N-(p-Cyanophenylcarbamoyl)-aminomethanesulfonatewhich possesses a D and B site, and is essentially tasteless inhibitsorganic bitter taste (caffeine) and sweet taste but not the bitter tasteassociated with potassium chloride. Taurine and β-alanine which bothpossess an AH, B array are both example of tastands.

Consequently, it is possible to tailor compounds by transforming knownsweeteners or known bitter compounds into essentially tastelessmolecules capable of either blocking the sweet taste response, theorganic bitter taste response, the inorganic bitter taste response orvarious combinations of each. Thus, a new and previously unanticipatedteaching of this invention is that the models of Goodman and coworkersand others can be used to predict tasteless compounds which can be usedas tastands as described herein. Such tastands are predicted to betasteless or nearly tasteless compounds which can be generated bytransformation of a sweet or bitter compound in a manner that eliminateshydrophobic interactions in the -z or X(G) areas (as defined by Goodmanor Tinti and Nofre) of the taste receptor(s). Such tastands are capableof blocking or inhibiting any one or any combination of the threetastes; sweet, organic bitter or inorganic bitter.

A molecule need only interact with one of the hydrogen bonding sitesdescribed above and have little or no hydrophobic interaction in theX(G) zone or -z zone to be a tastand. Frequently molecules capable ofinteracting with only one hydrogen bonding site and having a hydrophobicmoiety will possess sufficient flexibility (depending on size) to enterthe -z zone and will consequently be bitter tasting. Molecules with theability to hydrogen bond with more than one complementary site on areceptor will have a better chance of keeping hydrophobic groups out ofthe X(G) and -z zone, and consequently should have a high probability ofbeing a tastand.

According to the above logic, molecules which can interact with thereciprocal AH and/or B hydrogen bonding sites on a receptor as describedby Goodman (FIG. 3) and whose conformation and/or structure prevents anyhydrophobic interactions in the X (sweet taste) region and which also donot allow hydrophobic interactions in the -z (bitter taste) zone aretastands as defined herein.

Also, according to the above logic, molecules which can interact withthe reciprocal AH and/or B and/or D (or secondary sites) hydrogenbonding sites on a receptor as described by Tinti and Nofre (FIG. 1) andwhose conformation and/or structure prevents any hydrophobicinteractions with the G (sweet taste) region and which also do not allowhydrophobic interactions in the -z (bitter taste) zone which isdeveloped when the AH, B, D, G system of Tinti and Nofre is superimposedinto the AH, B, X system of Goodman (FIG. 4), are tastands.

As used herein and the appended claims AH, B, D, E₁, E₂, XH, Y, X, G, "Lshape", and the coordinates of x, y, z are defined hereinabove.##STR93## AH--Hydrogen Bond Donor Group B--Hydrogen Bond Acceptor Group

G--Hydrophobic Group

D--Hydrogen Bond Acceptor Group

XH--Weak Hydrogen Bond Donor Group

Y--Weak Hydrogen Bond Acceptor Group

E₁ --Weak Hydrogen Bond Acceptor Group

E₂ --Weak Hydrogen Bond Acceptor Group ##STR94## FIG. 2a-d. Preferredminimum energy conformations of (A)N-(L-aspartyl)-N'-(tetramethylcyclopentanoyl)-(R)-1,1-diaminoethane, (B)N-(L-aspartyl)-N'-(tetramethylcyclopentanoyl) (S)-1,1-diaminoethane, (C)L-aspartyl-D-alanyl-tetramethylcyclopentylamide and (D)L-aspartyl-L-alanyl-tetramethylcyclopentylamide. ##STR95##

The Goodman model for the sweet taste with L-aspartyl-L-phenylalaninemethyl ester superimposed. The φ bond, shown by the arrow, has beenrotated 40° from the X-ray diffraction structure. In addition, thehydrogen atoms have been added, with the standard bond lengths andangles. The AH-B and X groups of the molecule are illustrated accordingto the Shallenberger-Kier suggestions. ##STR96##

L-aspartyl-L-phenylalanine methyl ester in the "L-shape" proposed byGoodman for the sweet taste receptor superimposed into the 8-centeredmodel proposed by Tinti and Nofre.

Many of the above tastands exist as racemic mixtures (±), minus (-),plus (+), or diastereomeric optical isomers. It should be understoodthat the present invention. contemplates use of the tastands in eitherthe racemate or as the individual optical isomers. It is likely that oneor the other of the optical isomers of the racemic tastands possess thegreater, if not all, of the blocking or tastand activity. For example,it has been found that the (-) isomer of 2-(4-methoxyphenoxy)propionicacid possesses the majority of the activity that reduces undesirabletastes. The use of the most active isomer alone is advantageous in thatfar less tastand is needed to gain the desired reduction in undesirabletaste(s).

It has further been found that tastands described above and inparticular (-)-2-(4-methoxyphenoxy)propionic acid, in addition toinhibiting bitter taste also enhances the salty taste of sodiumcontaining compounds, if employed in sufficient concentrations. Thus,the present invention contemplates the preparation of eatablescontaining, for example, low sodium chloride and the tastands in anamount sufficient to enhance the salty taste of sodium chloride.

Moreover, the present invention contemplates the preparation of eatablescomprised of a mixture of substances having an undesirable taste such aspotassium chloride, magnesium chloride with sodium chloride and/orammonium chloride in conjunction with the tastands referred to herein inan amount that both reduces the undesirable taste(s) and enhances thesalty taste of the sodium chloride. Preferred eatable admixture productsof the invention comprise from slightly more than 0 up to about 300% byweight of substances with undesirable tastes such as, for example,potassium chloride and magnesium chloride and 0 to 50% by weight sodiumchloride in combination with effective concentrations of a tastand(s),typically 0,001% to about 50% preferable 0.1% to about 5%.

Moreover, the present invention contemplates the preparation of eatablessuch as breads, biscuits, pancakes, cakes, pretzels, snack foods, bakedgoods etc. prepared using for example potassium bicarbonate or potassiumcarbonate in place of the sodium salts as leavening agents inconjunction with a tastand in an amount sufficient to eliminate theundesirable taste associated with potassium ion or other tastes. Thetastand is typically present in an amount ranging from about 0.001% toabout 50% by weight, preferably about 0.1% to about 10% by weight, ofthe material with the undesirable taste. The present invention alsocontemplates the preparation of preservatives for eatables comprised ofthe potassium salts of benzoate, nitrate, nitrite, sulfate and sulfiteand so on, in conjunction with an appropriate concentration of atastand(s) to eliminate undesirable tastes in foodstuffs. Ideally thetastand is usually about 0.001% to about 10%, preferably about 0.1% toabout 5%, by weight of the material with the undesirable taste.

The present invention also contemplates the use of potassium salts offlavoring agents (such as for example glutamate) in place of sodiumsalts. Consequently monopotassium glutamate and/or guanalate and/orinosinate in conjunction with an appropriate amount of tastand toeliminate most if not all of the undesirable tastes, thus renderingmonopotassium glutamate essentially equivalent to monosodium glutamate.The tastand can be present from about 0.0000001% to about 300%,preferably from about 0.1% to about 5%, by weight of the material withthe undesirable taste.

The present invention also contemplates the preparation of medicamentssuch as aspirin, acetaminophen, ibuprofen, codeine, antibiotics, etc. inconjunction with a tastand(s) in sufficient concentration to remove orreduce the undesirable taste(s) of these materials. The tastand isusually 0.001% to about 50% by weight, preferably from about 0.5% toabout 5% by weight of the material with the undesirable taste. Thepresent invention also contemplates the preparation of eatables whichhave inherently undesirable tastes, such as unsweetened chocolate, inconjunction with a tastand in sufficient concentration to eliminate orreduce the bitterness of these products. The tastand is usually about0.001% to about 50% by weight, preferably about 0.2% to about 5%, byweight of the material with the undesirable taste.

As one skilled in the art would recognize, this reduction in theundesirable taste(s) could result in a reformulation of the product nowthat the undesirable taste(s) is reduced. A few specific examples ofthis would be:

1. The preparation of lower calorie chocolate products,

2. The preparation of lower calorie beverages,

3. The preparation of an eatable with a reduced quantity of highintensity sweeteners, or

4. The preparation of an eatable with a reduced quantity of lowintensity sweeteners.

5. The preparation of an eatable with a reduced quantity of highintensity sweeteners.

By the use of at least one tastand in an eatable with an undesirabletaste; a reformulation could be made which would result a reduction incalories and/or masking agents such as low intensity sweeteners, highintensity sweeteners, spices, and/or other flavorings.

The concentration of tastand employed to reduce the undesirable taste(s)in any given instance will vary depending principally on the particulartastand selected, the particular substance or substances with theundesirable taste(s), the extent of the reduction of the undesirabletaste(s) desired as well as the other tastes and flavors present in themixture. In most instances, concentrations of about 0.001 to 300% byweight, preferably about 0.05 to 5% of tastand to the material with theundesirable taste are satisfactory.

As an illustrative specific example, when the tastand is selected foruse with an admixture of sodium chloride and an undesirable tastingsubstance such as potassium chloride and/or magnesium chloride, it willgenerally be necessary to employ at least 0.2% by weight up to 10% byweight of the tastand based on the weight of the salt(s) to obtain boththe reduction of the undesirable taste(s) and salty taste enhancement.

The eatables to which the tastands of the invention can be added arewithout limitation and include both foodstuff and eatables havingessentially no food value such as pharmaceuticals, medicaments and othereatables. Therefore, the tastands of the present invention are effectivefor use with all substances which have an undesirable taste(s).Illustrative of substances with undesirable taste(s) with which thetaste modifiers of the invention can be used are potassium chloride,ammonium chloride, sodium chloride, magnesium chloride, halide salts,naringin, caffeine, urea, magnesium sulfate, saccharin, acetosulfames,aspirin, potassium benzoate, potassium bicarbonate, potassium carbonate,potassium nitrate, potassium nitrite, potassium sulfate, potassiumsulfite, potassium glutamate, food preservatives in theirphysiologically acceptable salts, ibuprofen, acetaminophen, antibiotics,codeine, cognac, unsweetened chocolate, cocoa beans, yogurt,preservatives, flavor enhancers, dietary supplements, gelling agents, Phcontrol agents, nutrients, processing aids, bodying agents, dispersingagents, stabilizers, colorings, coloring diluents, anticaking agents,antimicrobial agents, formulation aids, leavening agents, surface activeagents, anticaking agents, nutrient supplements, alkali, acids,sequestrants, denuding agents, general purpose buffers, thickeners,cooked out juice retention agents, color fixatives in meat and meatproducts, color fixatives in poultry and poultry products, doughconditioners, maturing agents, yeast foods, mold retardants,emulsifiers, texturizers, binders, water correctives, miscellaneous andgeneral purpose food additives, tableting aids, lye peeling agents,washing water agents, oxidizers, antioxidants, enzymes, extenders,fungicides, cake mixes, coffee, tea, dry mixes, non-dairy creamers,salts, animal glue adjuvant, cheese, nuts, meat and meat products,poultry and poultry product, pork and pork products, fish and fishproducts, vegetable and vegetable products, fruit and fruit products,smoked products such as meat, cheese fish, poultry, and vegetables,whipping agents, masticatory substances in chewing gums, doughstrengtheners, animal feed, poultry feed, fish feed, pork feed,defoaming agents, juices, liquors, substances or drinks containingalcohol, beverages including but not limited to alcoholic beverages andnon-alcoholic carbonated and/or non-carbonated soft drinks, whippedtoppings, bulking agents used in eatables including but not limited tostarches, corn solids, polysaccharides and other polymericcarbohydrates, icings, as well as potassium-containing ormetal-containing substances with undesirable tastes and the like.

While the above listing is extensive it is by no means all inclusive.Clearly one skilled in the art would recognize that many if not all ofthe:

A. sodium based salts or compounds, and/or,

B. sodium based salts or compounds made into their non-sodium basedcounterparts, and/or,

C. potassium based salts or compounds, and/or,

D. acids or acids made into their corresponding salts (sodium and/or nonsodium based compounds), and/or,

E. alkalis or alkalis made into their corresponding salts, and/or,

substances that are approved, at any time, as eatables by the Food andDrug Administration and/or that are GRAS as defined by the FlavorExtract Manufacturers' Association could then be made more palatable bythe use of the tastands taught herein (hereinafter and in the appendedclaims referred to as "material(s)"). These materials would or could bemade more palatable by the reduction or elimination of any undesirabletaste(s) associated with them. (Generally, sodium based salts are bettertasting than the corresponding non-sodium salts.) The use of tastandswith all of these materials as well as all of their anticipated uses ishereby anticipated by the teachings set forth herein.

Despite the breadth of this disclosure, one skilled in the art and theteaching taught herein shall be able to envision other examples.

EXAMPLE 1

An aqueous solution (1 L) containing 20 grams of a mixture comprised of95% potassium chloride and 5%

sodium chloride, and 0.05 grams (-)-2-(4-methoxyphenoxy)propionic acidsodium salt, gave a sodium chloride-like taste with virtually none ofthe bitterness normally associated with potassium chloride.

EXAMPLE 2

An aqueous solution (100 mL) containing 2 grams of potassium chlorideand 0.06 grams of L-aspartyl-L-phenylalanine monopotassium salt, gave aclean, salty taste virtually free of the bitter taste normallyassociated with potassium chloride.

EXAMPLE 3

An aqueous solution (1 L) containing 10 grams of sodium chloride and 1gram of (-)-2-(4-methoxyphenoxy)propionic acid sodium salt had asubstantially saltier taste than a 1% solution of sodium chloride alone.

EXAMPLE 4

An aqueous solution (1 L) containing 22.5 grams of potassium chlorideand 0.79 grams of 3-methoxyphenyl acetic acid sodium salt gave asubstantially bitter-free salty taste.

EXAMPLE 5

An aqueous solution (1 L) containing 20 grams of potassium chloride and0.2 grams of 2,6-dihydroxybenzoic acid potassium salt was nearly devoidof the characteristic potassium chloride bitter taste.

EXAMPLE 6

A solid preparation containing a mixture of potassium chloride (90grams), sodium chloride (10 grams) and (-)-2-(4-methoxyphenoxy)propionicacid sodium salt (0.25 grams) gave a clean salty sodium chloride-liketaste.

EXAMPLE 7

A solid preparation containing potassium chloride (80 grams), sodiumchloride (10 grams), magnesium chloride (10 grams) and(-)-2-(4-methoxyphenoxy)-propionic acid sodium salt (0.25 gram) gave awell-rounded, salty taste with virtually no bitterness.

EXAMPLE 8

The taste of lithium chloride was greatly improved by the addition of 1%by weight (-)-2-(4-methoxyphenoxy)propionic acid sodium salt. Thesaltiness was substantially increased.

EXAMPLE 9

Addition of 0.5% by weight of (-)-2-(4-methoxyphenoxy)propionic acidsodium salt to monopotassium glutamate produced a flavor almostidentical to monosodium glutamate. Virtually no bitter taste wasdetectable.

EXAMPLE 10

Addition of 6% by weight of (-)-2-(4-methoxyphenoxy)propionic acidsodium salt to aspirin gave a formulation that was slightly sour, withalmost no bitter taste or characteristic "aspirin"-like bitteraftertaste.

EXAMPLE 11

Addition of 3% by weight of (-)-2-(4-methoxyphenoxy)propionic acidsodium salt to aspirin gave a formulation substantially lacking thebitter taste of aspirin.

EXAMPLE 12

A solution containing 100 ppm caffeine and 10 ppm by weight (relative tocaffeine) of (-)-2-(4-methoxyphenoxy)propionic acid sodium salt wasalmost tasteless, and virtually all of the bitterness was removed.

EXAMPLE 13

The strong bitter taste of unsweetened chocolate was nearly eliminatedby the addition of 0.25% by weight of (-)-2-(4-methoxyphenoxy)propionicacid sodium salt.

EXAMPLE 14

Potassium benzoate containing 0.5% by weight(-)-2-(4-methoxyphenoxy)propionic acid sodium salt was added tofoodstuffs in place of sodium benzoate. There was no detectabledifference in the taste of the foodstuffs.

EXAMPLE 15

Potassium nitrate and potassium nitrite containing 0.5%(-)-2-(4-methoxyphenoxy)propionic acid sodium salt were added tofoodstuffs in place of the sodium salts. There was no detectabledifference in the taste.

EXAMPLE 16

Potassium bicarbonate containing 0.5% by weight(-)-2-(4-methoxyphenoxy)propionic acid sodium salt was used in place ofbaking soda for the baking of biscuits. There was essentially nobitterness detected.

EXAMPLE 17

Potassium bicarbonate/carbonate mixture containing 0.5% by weight(-)-2-(4-methoxyphenoxy)propionic acid sodium salt was used in place ofbaking powder for the preparation of pancakes. Essentially no bitternesswas detected.

EXAMPLE 18

When 10-20 ppm of (-)-2-(4-methoxyphenoxy)propionic acid sodium salt wasadded to black coffee, the strong bitter taste of the coffee was almostcompletely eliminated.

EXAMPLE 19

An aqueous solution (1 L) containing 20 grams of potassium chloride and0.6 grams of monosodium D-glutamate had substantially less bitternessthan a 2% solution of potassium chloride.

EXAMPLE 20

An aqueous solution (1 L) containing 20 grams of potassium chloride and1.2 grams of monopotassium D-glutamate had virtually none of thebitterness normally associated with potassium chloride.

EXAMPLE 21

When 0.25% by weight of hesperidin methyl chalcone (relative to KCl) wasadded to a 2% solution of KCl the bitterness of the KCl was reduced.

EXAMPLE 22

When 0.25% by weight (relative to the sodium nitrite) of(-)-2-(4-methoxyphenoxy)propionic acid sodium salt was added to 1%solution of sodium nitrite, the saltiness of the sodium nitrite wasenhanced.

EXAMPLE 23

When 5% by weight of hesperidin (relative to potassium chloride) wasadded to a 2% solution of potassium chloride and the mixture heated to40° C. the bitterness of the KCl was almost completely eliminated.

EXAMPLE 24

When 6.6% by weight of sodium D-aspartate (relative to potassiumchloride) was added to a 2% solution of potassium chloride the bittertaste of the potassium chloride was reduced and there was virtually noaftertaste.

EXAMPLE 25

When 0.06 grams of phenoxyacetic acid sodium salt was added to anaqueous solution containing 18 grams of potassium chloride and two gramsof sodium chloride, the bitter taste of the potassium chloride wassubstantially eliminated.

EXAMPLE 26

When 5% by weight (relative to potassium chloride) of2-methyl-3-nitroaniline was added to a 2% solution of potassium chloridethe bitter taste was virtually eliminated.

EXAMPLE 27

The bitter component of a 1% by weight aqueous calcium chloride solution(100 mL) was substantially eliminated by the addition of 0.2 grams of(-)-2-(4-methoxyphenoxy)propionic acid sodium salt.

EXAMPLE 28

The bitter component of a 1% by weight aqueous magnesium chloridesolution (100 mL) was reduced by the addition of 0.2 grams of(-)-2-(4-methoxyphenoxy)propionic acid sodium salt.

EXAMPLE 29

The bitter component of a 2% aqueous magnesium sulfate solution (100 mL)was greatly reduced by the addition of 0.04 grams of(-)-2-(4-methoxyphenoxy)propionic acid sodium salt.

EXAMPLE 30

When 100 ppm of (-)-2-(4-methoxyphenoxy)propionic acid sodium salt wasadded to whiskey, the strong burning sensation of the whiskey wassubstantially reduced.

EXAMPLE 31

When 100 ppm of (-)-2-(4-methoxyphenoxy)propionic acid sodium salt wasadded to cognac, the strong burning sensation of the cognac wassubstantially reduced.

EXAMPLE 32

When 100 ppm of (-)-2-(4-methoxyphenoxy)propionic acid sodium salt wasmixed with commercially prepared salsa sauce there was a substantialreduction in the hotness of the sauce.

EXAMPLE 33

When 10% (w/w relative to the saccharin) of racemic2-(4-methoxyphenoxy)propionic acid sodium salt was added to a 0.1%solution of sodium saccharin, virtually all of the bitterness wasremoved. There was no aftertaste noted.

EXAMPLE 34

When 1% (w/w, relative to the potassium nitrate) of(-)-2-(4-methoxyphenoxy)propionic acid sodium salt was added to a 3%aqueous potassium nitrate solution there was almost a completeelimination of the bitterness of the potassium nitrate.

EXAMPLE 35

When 0.25% (-)-2-(4-methoxyphenoxy)propionic acid sodium salt w/w wasadded to 10 grams La Victoria Hot Salsa the salsa sauce wassignificantly less harsh.

EXAMPLE 36

When a solution containing 25 ppm of a mixture having a ratio of 90parts (+)-2-(4-methoxyphenoxy)propionic acid sodium salt to 10 parts(-)-2-(4-methoxyphenoxy)propionic acid sodium salt and 100 ppm sodiumsaccharin there was no noticeable diminution of sweetness of the sodiumsaccharin and at the same time there was significantly less aftertaste.

EXAMPLE 37

When 0.5% by weight of potassium 2,4-dihydroxybenzoate (relative topotassium chloride) was added to 1% solution of potassium chloridevirtually all of the bitterness of the potassium chloride waseliminated.

EXAMPLE 38

When 0.5% by weight potassium 2,4-dihydroxybenzoate (relative to thepotassium chloride) was added to a 1% potassium chloride solution whichalso contains 2% sucrose, virtually all of the bitterness of thepotassium chloride was eliminated and the sucrose taste was notsubstantially affected.

EXAMPLE 39

When 25 mg of potassium 2,4-dihydroxybenzoate (69 ppm relative to thetotal volume of the cola) was added to a cola sweetened with saccharin,virtually all of the metallic aftertaste of the saccharin waseliminated.

EXAMPLE 40

When 25 ppm of potassium 2,4-dihydroxybenzoate was added to a solutioncontaining 100 ppm sodium saccharin there was no noticeable diminutionof sweetness of the saccharin and at the same time there wassignificantly less aftertaste.

EXAMPLE 41

Addition of 5% by weight (relative to the potassium chloride) ofdisodium ethylenediaminetetraacetic acid (EDTA) to an aqueous solutionof 2% potassium chloride greatly reduced the bitterness of potassiumchloride.

EXAMPLE 42

The bitterness of a 100 mL solution containing 0.11% caffeine wasreduced to the bitterness of a 0.08% solution of caffeine by theaddition of 100 mg potassium 2,4-dihydroxybenzoate.

EXAMPLE 43

A taste panel consisting of six tasters unanimously preferred potatochips salted with 1.6% w/w potassium chloride/sodiumchloride/L-aspartyl-L-phenylalanine potassium salt (90/10/3) over potatochips salted with 1.6% w/w potassium chloride/sodium chloride (90/10)due to substantially reduced bitterness.

EXAMPLE 44

An aqueous solution containing 1% sodium chloride and 0.005% potassium2,4-dihydroxybenzoate was saltier than an aqueous solution containingonly 1% sodium chloride.

EXAMPLE 45

The bitter taste of 200 mL of freshly brewed Sarks brand Espresso wasgreatly reduced by the addition of 20 mg of potassium2,4-dihydroxybenzoate.

EXAMPLE 46

The bitter and sour tastes of sodium acetylsalicylate was essentiallyabsent from an aqueous suspension comprised of sodium acetylsalicylate(0.5 gram), water (2 mL) and potassium 2,4-dihydroxybenzoate (0.375gram).

EXAMPLE 47

The bitterness of a 2% aqueous potassium chloride solution was nearlyeliminated by the addition of 1% by weight (relative to the potassiumchloride) of DL-3,4-dihydroxyphenylalanine, (DL-DOPA).

EXAMPLE 48

A sample of refried beans (100 gm) salted with potassium chloride (0.98gm), sodium chloride (0.42 gm) and sodium tartrate (0.15 gm) gave aclean, salty taste, almost completely devoid of bitterness, whencompared with a sample of 100 grams of refried beans salted only withpotassium chloride (0.98 gm) and sodium chloride (0.42 gm).

EXAMPLE 49

Addition of 5% by weight of sodium tartrate (relative to the potassiumchloride) to a 2% aqueous solution of potassium chloride significantlyreduced the bitterness associated with potassium chloride.

EXAMPLE 50

A sample of refried beans (100 gm) salted with potassium chloride (0.98gm), sodium chloride (0.42 gm) (a 70/30 ratio) and disodiumethylenediaminetetraacetic acid (0.7 gm) gave a clean, salty taste,virtually devoid of bitterness when compared with a sample of 100 gm ofrefried beans salted only with potassium chloride (0.98 gm) and sodiumchloride (0.42 gm).

EXAMPLE 51

The addition of 5 mg of sodium 2,4-dihydroxybenzoate to a cup of Tetleytea (200 mL) which had been sweetened with 40 mg of sodium saccharinalmost completely eliminated the bitter, metallic aftertaste of thesaccharin.

EXAMPLE 52

A solid, lyophilized salt preparation composed of 70 parts potassiumchloride, 30 parts sodium chloride and 0.35 parts potassium2,4-dihydroxybenzoate had a sharper initial salty taste, but wasotherwise virtually indistinguishable from lyophilized sodium chloride.

EXAMPLE 53

Addition of 5% by weight (relative to the potassium chloride) of sodium(+)-lactate to a 2% aqueous solution of potassium chloride significantlyreduced the bitterness associated with potassium chloride.

EXAMPLE 54

Addition of 5% by weight (relative to the potassium chloride) of sodiumascorbate to a 2% aqueous solution of potassium chloride significantlyreduced the bitterness associated with potassium chloride.

EXAMPLE 55

Addition of 1% by weight (relative to the potassium chloride) of sodiump-anisate to a 2% aqueous solution of potassium chloride reduced thebitterness associated with potassium chloride.

EXAMPLE 56

Addition of 70 mg of sodium 2,4-dihydroxybenzoate to 1 liter of a 0.04%solution of caffeine (400 mg) reduced the bitterness associated withcaffeine.

EXAMPLE 57

Addition of 0.5% by weight (relative to the potassium chloride) ofDL-methionine-methyl sulfonium chloride to a 2% aqueous solution ofpotassium chloride reduced the bitterness associated with potassiumchloride.

EXAMPLE 58

Addition of 6 grams of maltose to 100 mL of a 2% aqueous solution ofpotassium chloride reduced the bitterness of the potassium chloride.

EXAMPLE 59

To 50 grams of mashed potatoes was added 1.2 mL of a 100 mL solutioncontaining potassium chloride (17.3 gm), sodium chloride (1.9 gm) and(+)-2-(4-methoxyphenoxy)propionic acid sodium salt (0.8 gm). The mashedpotatoes had a clean, salty taste with almost no bitter taste associatedwith potassium chloride.

EXAMPLE 60

Addition of 8 mg of xanthosine 5' monophosphate to 100 mL of a 2%aqueous solution of potassium chloride reduced the bitterness ofpotassium chloride and enhanced the saltiness.

EXAMPLE 61

Addition of 5% by weight (relative to the potassium chloride) of sodium2-hydroxyphenylacetate to a 2% aqueous solution of potassium chloridesignificantly reduced the bitterness associated with potassium chloride.

EXAMPLE 62

Addition of 0.5% by weight (relative to the potassium chloride) ofsodium 1-hydroxy-2-naphthoate to a 2% aqueous solution of potassiumchloride significantly reduced the bitterness associated with potassiumchloride.

EXAMPLE 63

Addition of 1% by weight (relative to the potassium chloride) of sodium3-hydroxy-2-naphthoate to a 2% aqueous solution of potassium chloridesignificantly reduced the bitterness associated with potassium chloride.

EXAMPLE 64

Addition of 5% by weight (relative to the potassium chloride) of sodium2,4,6-trihydroxybenzoate to a 2% aqueous solution of potassium chloridesignificantly reduced the bitterness associated with potassium chloride.

EXAMPLE 65

Addition of 0.5% by weight (relative to the potassium chloride) ofsodium 4-aminosalicylate to a 2% aqueous solution of potassium chloridereduced the bitterness associated with potassium chloride.

EXAMPLE 66

Addition of 1% by weight (relative to the potassium chloride) of sodiumanthranilate to a 2% aqueous solution of potassium chloride reduced thebitterness associated with potassium chloride.

EXAMPLE 67

Addition of 0.5% by weight (relative to the potassium chloride) ofsodium aniline-2-sulfonate to a 2% aqueous solution of potassiumchloride reduced the bitterness associated with potassium chloride.

EXAMPLE 68

Addition of 3.5% by weight (relative to the potassium chloride) of3-methoxyphenylacetic acid to a 2.25% aqueous solution of potassiumchloride, reduced the bitterness associated with potassium chloride.

EXAMPLE 69

Addition of 0.65% by weight (relative to the potassium chloride) ofneodiosmin to a 2% aqueous solution of potassium chloride reduced thebitterness associated with potassium chloride.

EXAMPLE 70

Health Valley Chicken Broth (unsalted, 200 mL) salted with potassiumchloride (0.8 gm), sodium chloride (0.2 gm) and sodium(+)-2-(4-methoxyphenoxy)propionate (0.03 gm) (a 80/20/3 ratio), gave awell salted flavor virtually free of any bitter taste.

EXAMPLE 71

Addition of 25 mg sodium 2,4-dihydroxybenzoate to one can of C&C DietCola (354 mL) containing 126 mg sodium saccharin reduced the aftertasteassociated with sodium saccharin.

EXAMPLE 72

Addition of 6.6% by weight (relative to the potassium chloride) ofsodium syringate to a 2% aqueous solution of potassium chloride reducedthe bitterness associated with potassium chloride.

EXAMPLE 73

Addition of 0.1 gram of guanosine to a 100 mL aqueous solutioncontaining 0.1 gram of aspirin significantly reduced the bitternessassociated with the aspirin.

EXAMPLE 74

Campbell's Chicken Broth (unsalted, 100 mL) was salted with potassiumchloride (1.8 gm), sodium chloride (0.2 gm) and potassium2,4-dihydroxybenzoate (0.01 gm) (a ratio of 90/10/0.5), gave a good,salty tasting broth essentially devoid of bitterness.

EXAMPLE 75

Addition of 5% by weight (relative to the potassium chloride) of3,4-dihydroxyphenylacetic acid sodium salt to a 2% aqueous solution ofpotassium chloride reduced the bitterness associated with potassiumchloride.

EXAMPLE 76

The bitterness associated with potassium chloride was reduced when a 2%aqueous solution of potassium chloride was saturated with uric acid.

EXAMPLE 77

Addition of 3.7% by weight (relative to the potassium chloride) ofguanosine to a 2% aqueous solution of potassium chloride reduced thebitterness associated with potassium chloride.

EXAMPLE 78

The bitterness associated with potassium chloride was reduced when a 2%aqueous solution of potassium chloride was saturated with uracil.

EXAMPLE 79

The bitterness associated with potassium chloride was reduced when a 2%aqueous solution of potassium chloride was saturated with d-biotin.

EXAMPLE 80

The bitterness associated with potassium chloride was reduced when a 2%aqueous solution of potassium chloride was saturated withDL-dihydroorotic acid.

EXAMPLE 81

A sample of 100 gm of unsalted refried beans salted with potassiumchloride (0.98 gm), sodium chloride (0.42 gm), potassium2,4-dihydroxybenzoate (5.0 mg), and disodium ethylenediaminetetraaceticacid (0.7 gram, 5 mL of a 14% solution, adjusted to pH 6.8) gave aclean, salty taste essentially devoid of bitterness.

EXAMPLE 82

The bitter taste of a 2% aqueous solution of potassium chloride wasreduced by the addition of 20% by weight (relative to the potassiumchloride) of L-threonine.

EXAMPLE 83

The bitter taste of a 2% aqueous solution of potassium chloride wasnearly eliminated by the addition of 20% by weight (relative to thepotassium chloride) of sodium malate.

EXAMPLE 84

Hains No Salt Vegetable Soup (100 gm) salted with potassium chloride(0.9 gm), sodium chloride (0.1 gm) and potassium 2,4-dihydroxybenzoate(0.005 gm) (a ratio of 90/10/.5), gave a salty, good tasting soupbasically devoid of bitterness.

EXAMPLE 85

Hains No Salt Vegetable Soup (100 gm) salted with potassium chloride(0.9 gm), sodium chloride (0.1 gm) and sodium 2,4,6-trihydroxybenzoate(0,005 gm) (a ratio of 90/10/0.5), gave a salty, good tasting souppractically devoid of bitterness.

EXAMPLE 86

Hains No Salt Vegetable Soup (100 gm) salted with potassium chloride(0.9 gm), sodium chloride (0.1 gm), L-aspartyl-L-phenylalanine potassiumsalt (0.015 gm) and potassium 2,4-dihydroxybenzoate (0.0025 gm) (a ratioof 90/10/1.5/0.25), gave a taste essentially without bitterness. It wasmore salty than soup salted with potassium chloride (0.9 gm), sodiumchloride (0.1 gm) and L-aspartyl-L-phenylalanine potassium salt (0.03gm) (a ratio of 90/10/3) or potassium chloride (0.9 gm), sodium chloride(0.1 gm) and potassium 2,4-dihydroxybenzoate (0.005 gm) (a ratio of90/10/0.5).

EXAMPLE 87

Charles brand unsalted potato chips (100 gm) salted with potassiumchloride (1.6 gm) and potassium 2,4-dihydroxybenzoate (0,008 gm) gave agood salty taste that was essentially free of any bitter taste.

EXAMPLE 88

Charles brand unsalted potato chips (100 gm) salted with potassiumchloride (0.98 gm), sodium chloride (0.42 gm) and potassium2,4-dihydroxybenzoate (0.005 gm) (a ratio of 70/30/0.35) gave a goodsalty taste devoid of bitterness. These chips were essentiallyindistinguishable from chips salted with sodium chloride.

EXAMPLE 89

Charles brand unsalted potato chips (100 gm) salted with potassiumchloride (0.67 gm), sodium chloride (0.67 gm) and potassium2,4-dihydroxybenzoate (0.0034 gm) (a ratio of 50/50/0.25) gave a goodsalty taste as if the chips were prepared with pure sodium chloride.

EXAMPLE 90

A sample of unsalted refried beans (100 gm) salted with potassiumchloride (0.98 gm), sodium chloride (0.42 gm) (a ratio of 70/30) andsodium (+)-lactate (0.1 gm) gave a clean, salty taste like that ofsodium chloride.

EXAMPLE 91

A sample of unsalted refried beans (100 gm) salted with potassiumchloride (1.12 gm), sodium chloride (0.48 gm), potassium2,4-dihydroxybenzoate (0.0056 gm) (a ratio of 70/30/0.35) and 0.3 gmsodium (+)-lactate gave a taste essentially devoid of bitterness. It wasalso more salty then refried beans salted with potassium chloride (1.2gm), sodium chloride (0.4 gm) (a ratio of 70/30) and sodium (+)-lactate(0.1 gm).

EXAMPLE 92

A sample of unsalted refried beans (100 gm) salted with potassiumchloride (1.2 gm), sodium chloride (0.4 gm) (a ratio of 70/30) andsodium (+)-lactate (0.3 gm) gave a sodium chloride like taste. It wasalso more salty than refried beans salted with potassium chloride (1.2gm), sodium chloride (0.4 gm) (a ratio of 70/30) and sodium (+)-lactate(0.1 gm).

EXAMPLE 93

The bitter taste of a 1000 ppm solution (100 mL) of caffeine wassubstantially reduced by the addition of guanosine (20 mg).

EXAMPLE 94

The bitter taste of a 1000 ppm solution (100 mL) of caffeine was almostcompletely eliminated by the addition of inosine (20 mg).

EXAMPLE 95

An aqueous solution (100 mL) containing potassium chloride (2.0 g) andN-(L-aspartyl)-p-aminobenzoic acid monopotassium salt (0.1 g) gave asalty taste without the bitterness normally associated with potassiumchloride.

EXAMPLE 96

An aqueous solution (100 mL) containing potassium chloride (2.0 g) andN-(L-aspartyl)-p-aminobenzoic acid monopotassium salt (0.02 g) gave asalty taste, with a substantially decrease of bitterness from potassiumchloride.

EXAMPLE 97

A solid preparation containing a mixture of potassium chloride (1.8 g),sodium chloride (0.2 g) and N-(L-aspartyl)-p-aminobenzoic acidmonopotassium salt (0.02 g) gave a clean salty sodium chloride-liketaste.

EXAMPLE 98

A solid lyophilized from a aqueous solution containing potassiumchloride (1.8 g), sodium chloride (0.2 g) andN-(L-aspartyl)-o-aminobenzoic acid monopotassium salt (0.1 g) gave aclean sodium chloride-like taste with virtually none of the bitternessnormally associated with potassium chloride.

EXAMPLE 99

A solid obtained from a aqueous solution containing potassium chloride(1.8 g), sodium chloride (0.02 g) and N-(L-aspartyl)-o-aminobenzoic acidmonopotassium salt gave a bitterness-free salty taste.

EXAMPLE 100

When 5% by weight of potassium L-aspartyl-L-tyrosine (relative topotassium chloride) was added to a 2% solution of potassium chloride thebitter taste of potassium chloride was completely eliminated.

EXAMPLE 101

When 1% by weight of potassium L-aspartyl-L-tyrosine (relative topotassium chloride) was added to a 2% solution of potassium chloride thebitter taste of potassium chloride was virtually eliminated.

EXAMPLE 102

Addition of 0.5% by weight of potassiumN-(p-cyanophenyl-carbamoyl)-L-aspartyl-L-phenylalanine (relative topotassium chloride) to a 2% of potassium chloride solution gave a saltytaste with free of the bitter taste.

EXAMPLE 103

Addition of 0.1% by weight of potassiumN-(p-cyanophenyl-carbamoyl)-L-aspartyl-L-phenylalanine (relative topotassium chloride) to an aqueous solution of 2% potassium chloridesubstantially eliminated the bitter taste of potassium chloride.

EXAMPLE 104

When 0.5% by weight of potassiumN-(p-nitrophenyl-carbamoyl)-L-aspartyl-L-phenylalanine (relative topotassium chloride) was added to a 2% potassium chloride solution, thebitter taste of potassium chloride was virtually eliminated.

EXAMPLE 105

When 0.1% by weight of potassiumN-(p-nitrophenylcarbamoyl)-L-aspartyl-L-phenylalanine (relative topotassium chloride) was added to a 2% solution of potassium chloride, nobitterness was essentially detected.

EXAMPLE 106

An aqueous solution (100 mL) containing potassium chloride (2.0 g) andpotassium L-β-aspartyl-L-phenylalanine (0.1 g) gave a salty taste withno bitter taste associated with potassium chloride.

EXAMPLE 107

An aqueous solution (100 mL) containing potassium chloride (2.0 g) andpotassium L-β-aspartyl-L-phenylalanine (0.02 g) gave a salty taste witha substantial reduction of bitter taste.

EXAMPLE 108

Addition of potassium (-)-2-(4-methoxyphenoxy) propionate (500 mg, 10times relative to caffeine) to a 0.05% of caffeine (100 mL) completelyeliminated the bitter taste, with a lingering sweet after taste only.

EXAMPLE 109

Addition of potassium (-)-2-(4-methoxyphenoxy) propionate (250 mg, 5times relative to caffeine) to a 0.05% of caffeine (100 mL)significantly reduced the bitter taste of caffeine with a sweet aftertaste.

EXAMPLE 110

A solid lyophilized from a solution containing potassium chloride (1.8g), sodium chloride (0.2 g) and potassiumN-(p-cyanophenyl-carbamoyl)-L-aspartyl-L-phenylalanine (0.010 g) gave asodium chloride-like taste with virtually none of the bitternessnormally associated with potassium chloride.

EXAMPLE 111

A strong bitter taste was completely eliminated when potassiumN-(p-cyanophenyl-carbamoyl)-L-aspartyl-L-phenylalanine (500 mg, 10 timesrelative to caffeine) was added to a 0.05% solution of caffeine (100mL).

EXAMPLE 112

A strong bitter taste was nearly eliminated when potassiumN-(p-cyanophenyl-carbamoyl)-L-aspartyl-L-phenylalanine (250 mg, 5 timesrelative to caffeine) was added to a 0.05% caffeine solution (100 mL).

EXAMPLE 113

An aqueous solution (100 mL) containing caffeine (50 mg) and potassiumN-(p-nitrophenyl-carbamoyl)-L-aspartyl-L-phenylalanine (500 mg) wasslightly sweet and completely devoid of the bitter taste.

EXAMPLE 114

An aqueous solution (100 mL) containing caffeine (50 mg) and potassiumN-(p-nitrophenyl-carbamoyl)-L-aspartyl-L-phenylalanine (250 mg) gavealmost no bitter taste with a slightly sweet taste.

EXAMPLE 115

When 1% by weight of potassium 2,4,6-trihydroxybenzoate (relative topotassium chloride) was added to a 2% solution of potassium chloride thebitterness of potassium chloride was completed eliminated.

EXAMPLE 116

When 0.5% by weight of potassium 2,4,6-trihydroxybenzoate (relative topotassium chloride) was added to a 2% solution of potassium chloride asalty taste was obtained with no bitterness associated with potassiumchloride.

EXAMPLE 117

When 0.25% by weight of potassium 2,4,6-trihydroxybenzoate (relative topotassium chloride) was added a potassium chloride solution (2%), asalty and free of bitterness taste were given.

EXAMPLE 118

A solid lyophilized from a aqueous solution of potassium chloride (1.6g), sodium chloride (0.4 g) and potassium 2,4,6-trihydroxybenzoate (0.01g) gave a sodium chloride-like taste with none of the bitternessassociated with potassium chloride.

EXAMPLE 119

A solid lyophilized from a solution containing potassium chloride (1.6g), sodium chloride (0.4 g) and potassium 2,4,6-trihydroxybenzoate(0.005 g) gave a salty taste virtually free of bitter taste associatedwith potassium chloride.

EXAMPLE 120

When 5% by weight of taurine (relative to potassium chloride) was addedto a 2% solution of potassium chloride the bitter taste of potassiumchloride was completely eliminated.

EXAMPLE 121

The sweetness of a 4% solution of sugar (100 mL) was significantlyreduced by the addition of N-(L-aspartyl)-o-aminobenzoic acidmonopotassium salt (40 mg).

EXAMPLE 122

The sweetness was completely eliminated whenN-(L-aspartyl)-o-aminobenzoic acid monopotassium salt (200 mg) was addedto or 4% solution of sugar (100 mL).

EXAMPLE 123

The sweetness of a 4% solution of sugar (100 mL) was reduced to thesweetness of a 2% solution of sugar by addition ofL-aspartyl-L-phenylalanine monopotassium salt (1.2 g, 30% relative tosugar).

EXAMPLE 124

The sweetness of a 0.04% solution of Aspartame® (100 mL) was slightlyreduced and the lingering taste of Aspartame® eliminated by addition ofL-aspartyl-L-phenylalanine monopotassium salt (400 mg, 10 times relativeto Aspartame®).

EXAMPLE 125

An aqueous solution (75 mL) containing glycerol (12 grams) and taurine(0.37 grams) wherein the burning aftertaste of the glycerol issubstantially decreased or eliminated.

EXAMPLE 126

An aqueous solution (75 mL) adjusted to a pH=6 containing glycerol (12grams) and L-aspartyl-L-phenylalanine (0.62 grams) wherein the burningaftertaste of the glycerol is substantially decreased or eliminated andthe mixture tasted somewhat sweeter.

EXAMPLE 127

An aqueous solution (75 mL) containing glycerol (12 grams) and potassium2,4-dihydroxybenzoate (0.12 grams) wherein the burning aftertaste of theglycerol is decreased.

EXAMPLE 128

An aqueous solution (75 mL) containing glycerol (12 grams) and β-alanine(0.60 grams) wherein the burning aftertaste of the glycerol isdecreased.

EXAMPLE 129

The aftertaste of L-aspartyl-L-phenylalanine methyl ester (Aspartame®)used to sweetened a Diet Coke® (354 mL can) was substantially eliminatedby the addition of 7.5 mg of L-aspartyl-L-phenylalanine.

EXAMPLE 130

The aftertaste of the L-aspartyl-L-phenylalanine methyl ester(Aspartame®) used to sweetened a Diet Pepsi® (354 mL can) wassubstantially eliminated by the addition of 7.5 mg ofL-aspartyl-L-phenylalanine.

EXAMPLE 131

The aftertaste of the saccharin used to sweeten C&C Diet Cola®(354 mLcan) was substantially eliminated by the addition of 10 mg of taurine.

EXAMPLE 132

When 5% by weight of β-alanine (relative to potassium chloride) wasadded to a 2% solution of potassium chloride the bitter taste ofpotassium chloride was completely eliminated.

EXAMPLE 133

An aqueous solution (100 mL) containing potassium chloride (2.0 g) andN-(L-aspartyl)-α-amino-cyclopentanecarboxylic acid mono-potassium salt(0.1 g) eliminated almost all of the bitterness associated withpotassium chloride.

EXAMPLE 134

A solid lyophilized from an aqueous solution containing potassiumchloride (1.8 g), sodium chloride (0.2 g) andN-(L-aspartyl)-α-amino-cyclopentanecarboxylic acid mono-potassium salt(0.1 g) gave a salty sodium chloride-like taste which was free ofbitterness associated with potassium chloride.

EXAMPLE 135

A solid lyophilized from a solution containing potassium chloride (1.8g), sodium chloride (0.2 g) andN-(L-aspartyl)-α-amino-cyclopentanecarboxylic acid mono-potassium salt(0.02 g) gave a clean salty taste, virtually free of the bitterness frompotassium chloride.

EXAMPLE 136

A solid lyophilized from a solution containing potassium chloride (1.8g), sodium chloride (0.2 g) andN-(L-aspartyl)-α-amino-cyclooctanecarboxylic acid mono-potassium salt(0.1 g) gave a salty taste. The bitter taste of potassium chloride wasessentially eliminated.

EXAMPLE 137

Addition of 5% by weight of β-alanine (relative to potassium chloride)to a 2% solution of potassium chloride eliminated the bitter taste ofpotassium chloride.

EXAMPLE 138

A powder lyophilized from an aqueous mixture of potassium chloride (1.8g), sodium chloride (0.2 g) and β-alanine (0.1 g) gave a clean sodiumchloride-like taste.

EXAMPLE 139

A powder lyophilized from a mixture of potassium chloride (1.8 g),sodium chloride (0.2 g) and β-alanine (0.02 g) gave a salty tastewithout the bitterness normally associated with potassium chloride.

EXAMPLE 140

When 5% by weight of potassiumN-(phenylcarbamoyl)-L-aspartyl-L-phenylalanine (relative to potassiumchloride) was added to a 2% solution of potassium chloride, thebitterness associated with potassium chloride was eliminated.

EXAMPLE 141

An aqueous solution (100 mL) containing L-ornithine-β-alaninedihydrochloride (0.1 g) and potassium chloride (2.0 g) at pH 6.1 gave asalty taste without bitterness.

EXAMPLE 142

A powder lyophilized from an aqueous solution containing potassiumchloride (1.8 g), sodium chloride (0.2 g) and L-ornithine-β-alaninedihydrochloride at pH 6.1 gave a salty taste with free of bitterness.

EXAMPLE 143

A powder lyophilized from an aqueous solution containing potassiumchloride (1.8 g), sodium chloride (0.2 g) and L-ornithine-β-alaninedihydrochloride (0.02 g) at pH 6.1 virtually eliminated the bitternessassociated with potassium chloride and gave a salty taste.

EXAMPLE 144

Addition of 1% by weight of β-aminoethyl phosphonic acid (relative topotassium chloride) to a 2% potassium chloride solution gave a saltytaste free of the bitter taste associated with potassium chloride.

EXAMPLE 145

Addition of.5% by weight of β-aminoethyl phosphonic acid (relative topotassium chloride) to a 2% solution of potassium chloride gave a saltytaste free of the bitter taste associated with potassium chloride.

EXAMPLE 146

A solid lyophilized from the mixture of potassium chloride (1.8 g),sodium chloride (0.2 g) and β-aminoethyl phosphonic acid (0.02 g) gave aclean salty taste without the bitter taste associated with potassiumchloride.

EXAMPLE 147

A solid made from a solution of potassium chloride (1.8 g), sodiumchloride (0.2 g) and β-aminoethyl phosphonic acid (0.1 g) was completelyfree of the bitterness from potassium chloride.

EXAMPLE 148

The bitterness associated with potassium chloride was completelyeliminated when 2-amino tere-phthalic acid potassium salt (0.02 g, 1%relative to the potassium chloride) was added to a 2% solution ofpotassium chloride (100 mL).

EXAMPLE 149

The bitterness associated with potassium chloride was completelyeliminated when 2-amino tere-phthalic acid potassium salt (0.1 g, 5%relative to the potassium chloride) was added to a 2% solution ofpotassium chloride (100 mL).

EXAMPLE 150

When taurine (0.05 g, 50% relative to Acesulfame K) was added to a 0.1%solution of Acesulfame K (100 mL) the aftertaste associated withAcesulfame K was substantially decreased.

EXAMPLE 151

When taurine (0.10 g) was added to an aqueous solution containingAcesulfame K (0.10 g), the sweetness was decreased and the aftertastewas completely eliminated.

EXAMPLE 152

Addition of β-alanine (0.01 g, 10% relative to Acesulfame K) in a 0.1%solution of Acesulfame K (100 mL) fully eliminated the off-tasteassociated with Acesulfame K and gave a clean sweet taste.

EXAMPLE 153

Addition of β-alanine (0.05 g, 50% relative to Acesulfame K) in a 0.1%solution of Acesulfame K fully eliminated the aftertaste of Acesulfame Kand decreased the sweet potency by about 70%.

EXAMPLE 154

When β-alanine (0.025 g) was added to a can of Shasta diet cola (354mL), the off-taste associated with sodium saccharin and/or Aspartame wassubstantially decreased.

EXAMPLE 155

When β-alanine (0.02 g) was added to a can of VONS sugar-free cola (355mL) containing sodium saccharin (0.107 g), the aftertaste associatedwith saccharin was completely eliminated.

EXAMPLE 156

Addition of β-alanine (0.02 g) to a can of diet Pepsi (355 mL) reducedsignificantly the aftertaste associated with Aspartame.

EXAMPLE 157

Addition of 50% by weight of potassium L-aspartyl-L-phenylalanine(relative to Acesulfame K) to a 0.1% solution of Acesulfame K reducedboth the sweetness and aftertaste associated with Acesulfame K.

EXAMPLE 158

When 5% by weight of L-aspartyl-L-aspartic acid was added (relative toKCl) to a 2% solution of KCl adjusted to a pH=6, the bitterness of theKCl was virtually eliminated.

EXAMPLE 159

When two parts of acetominophen is blended with one part of5-hydroxyflavone the resultant mixture is substantially reduced inbitterness.

EXAMPLE 160

When one part of chlorpheniramine maleate is blended with one part of5-hydroxyflavone the resultant mixture is substantially reduced inbitterness.

EXAMPLE 161

When one part of pseudoephedrine hydrochloride is blended with one partof 5-hydroxyflavone the resultant mixture is substantially reduced inbitterness.

EXAMPLE 162

When one part of guaifenesin is blended with one part of5-hydroxyflavone the resultant mixture is substantially reduced inbitterness.

EXAMPLE 163

When one part of phenylpropanolamine HCl is blended with one part of5-hydroxyflavone the resultant mixture is reduced in bitternessapproximately fifty percent.

EXAMPLE 164

When one part of pseudoephedrine hydrochloride is blended with one partof 5,7-dihydroxyflavone the resultant mixture is reduced in bitternessmore than fifty percent.

It is claimed:
 1. A composition comprising an eatable having at leastone taste selected from bitter and metallic, and at least one tastand ina substantially tasteless amount of about 0.0000001 to about 300% byweight, based on the weight of the eatable, which amount is sufficientto reduce said at least one bitter and metallic taste, said tastandbeing selected from the group consisting of compounds which aresubstantially tasteless in the amount used and have the structure:##STR97## wherein n and k are independently selected from 0, 1 or 2;each Y is independently selected from N, O, and S; Q is selected fromthe group consisting of H, trifluoromethyl, halogen, cyano; andsubstituted or unsubstituted alkyl, alkylene, branched alkyl, branchedalkylene, aryl, aralkyl, cycloalkyl, acyl, benzoyl, alkoxy, aryloxy,heterocyclic, polycyclic; p and q are 1 when Y is O, p and q areindependently selected from 1 and 2 when Y is S, and p and q areindependently selected from 2 and 3 when Y is N; R which may be the sameor different when p>1 and R' which may be the same or different when q<1are independently selected from the group consisting of H,trifluoroacetyl; and substituted or unsubstituted alkyl, dialkyl,aralkyl, aryl, diaryl, acyl, cycloalkyl, benzoyl, alkyloxycarbonyl,aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, amidines,alkylamidines, arylamidines, a monosaccharide, a disaccharide, atrisaccharide, an oligosaccharide, phosphorylated saccharides, arylacyl,alkylene, heterocyclic and polycyclic; and following three structuresD-2: ##STR98## wherein Z and Z' are independently selected from thegroup consisting of OH, --O⁻ X⁺, OR", NH₂, NHR", N(R")₂ ; R" is selectedfrom the group consisting of alkyl, branched alkyl, aryl, aralkyl,alkaryl, cycloalkyl, substituted alkyl, substituted cycloalkyl,substituted aryl, substituted aralkyl and substituted alkaryl, and R'"is selected from alkyl, branched alkyl, aryl, aralkyl, alkaryl,cycloalkyl, substituted alkyl, substituted cycloalkyl, substitutedaralkyl, substituted alkaryl, and an amino acid side chain; where CH--CHor CH₂ --CH₂ bonds exist the level of unsaturation may be increased byremoving one or more hydrogen atoms from the carbon atoms participatingin the CH--CH or CH₂ --CH₂ bond, and X⁺ is selected from H⁺ or aphysiologically acceptable cation; and physiologically acceptable saltsof all of the foregoing.
 2. A composition comprising an eatableaccording to claim 1 wherein the eatable having at least one taste is asubstance having a bitter taste.
 3. A composition according to claim 2wherein the eatable having at least one taste comprises potassiumchloride.
 4. A composition comprising an eatable according to claim 1wherein the at least one tastand is selected from the group consistingof:1. L-aspartyl-L-phenylalanine,
 2. aminomalonyl-L-phenylalanine, 3.L-aspartyl-D-alanine,
 4. L-aspartyl-D-serine,
 5. 5.L-glutamyl-L-phenylalanine,6. N-(L-aspartyl)-p-aminobenzoic acid, 7.N-(L-aspartyl)-o-aminobenzoic acid,
 8. L-aspartyl-L-tyrosine, 9.N-(p-cyanophenylcarbamoyl)-L-aspartyl-L-phenylalanine, 10.N-(p-nitrophenylcarbamoyl)-L-aspartyl-L-phenylalanine, 11.L-α-aspartyl-L-phenylalanine methyl ester, 12.L-aspartyl-p-hydroxyanilide,
 13. L-α-aspartyl-L-phenylalanine, 14.L-aspartyl-L-serine methyl ester,
 15. L-aspartyl-D-tyrosine methylester,
 16. L-aspartyl-L-threonine methyl ester, 17.L-aspartyl-L-aspartic acid,and physiologically acceptable salts of anyand/or all of the foregoing. A method of making a composition from aneatable possessing at least one taste selected from bitter and metallic,which method comprises incorporating in or ingesting with said eatableat least one tastand in a substantially tasteless amount of about0.0000001 to about 300% by weight, based on the weight of the eatable,which amount is sufficient to reduce said at least one bitter and/ormetallic taste, said tastand being selected from the group consisting ofcompounds which are substantially tasteless in the amount used and havethe structure: ##STR99## wherein n and k are independently selected from0, 1 or 2; each Y is independently selected from N, O, and S; Q isselected from the group consisting of H, trifluoromethyl, halogen,cyano; and substituted or unsubstituted alkyl, alkylene, branched alkyl,branched alkylene, aryl, aralkyl, cycloalkyl, acyl, benzoyl, alkoxy,aryloxy, heterocyclic, polycyclic; p and q are 1 when Y is O, p and qare independently selected from 1 and 2 when Y is S, and p and q areindependently selected from 2 and 3 when Y is N; R which may be the sameor different when p>1 and R' which may be the same or different when q<1are independently selected from the group consisting of H,trifluoroacetyl; and substituted or unsubstituted alkyl, dialkyl,aralkyl, aryl, diaryl, acyl, cycloalkyl, benzoyl, alkyloxycarbonyl,aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, amidines,alkylamidines, arylamidines, a monosaccharide, a disaccharide, atrisaccharide, an oligosaccharide, phosphorylated saccharides, arylacyl,alkylene, heterocyclic and polycyclic; and following three structuresD-2: ##STR100## wherein Z and Z' are independently selected from thegroup consisting of OH, --O⁻ X⁺, OR", NH₂, NHR", N(R")₂ ; R" is selectedfrom the group consisting of alkyl, branched alkyl, aryl, aralkyl,alkaryl, cycloalkyl, substituted alkyl, substituted cycloalkyl,substituted aryl, substituted aralkyl and substituted alkaryl, and R'"is selected from alkyl, branched alkyl, aryl, aralkyl, alkaryl,cycloalkyl, substituted alkyl, substituted cycloalkyl, substitutedaralkyl, substituted alkaryl, and an amino acid side chain; where CH--CHor CH₂ --CH₂ bonds exist the level of unsaturation may be increased byremoving one or more hydrogen atoms from the carbon atoms participatingin the CH--CH or CH₂ --CH₂ bond, and X⁺ is selected from H⁺ or aphysiologically acceptable cation; and physiologically acceptable saltsof all of the foregoing.
 6. A method in accordance with claim 5 whereinthe eatable having at least one taste is a substance having a bittertaste.
 7. A method in accordance with claim 6 wherein the eatable havingat least one taste comprises potassium chloride.
 8. A method inaccordance with claim 5 wherein the at least one tastand is selectedfrom the group consisting of:1. L-aspartyl-L-phenylalanine, 2.aminomalonyl-L-phenylalanine,
 3. L-aspartyl-D-alanine, 4.L-aspartyl-D-serine,
 5. L-glutamyl-L-phenylalanine, 6.N-(L-aspartyl)-p-aminobenzoic acid,7. N-(L-aspartyl)-o-aminobenzoicacid,
 8. L-aspartyl-L-tyrosine, 9.N-(p-cyanophenylcarbamoyl)-L-aspartyl-L-phenylalanine, 10.N-(p-nitrophenylcarbamoyl)-L-aspartyl-L-phenylalanine, 11.L-α-aspartyl-L-phenylalanine methyl ester, 12.L-aspartyl-p-hydroxyanilide,
 13. L-α-aspartyl-L-phenylalanine, 14.L-aspartyl-L-serine methyl ester,
 15. L-aspartyl-D-tyrosine methylester,
 16. L-aspartyl-L-threonine methyl ester, 17.L-aspartyl-L-aspartic acid,and physiologically acceptable salts of anyand/or all of the foregoing.
 9. A composition as claimed in claim 1wherein the eatable having a bitter or metallic taste comprises at leastone pharmaceutical having a bitter or metallic taste.
 10. A compositionas claimed in claim 1 wherein the eatable having a bitter or metallictaste is selected from the group consisting of the following compoundswhich have a bitter or metallic taste: amino acids, peptides,polypeptides and proteins.
 11. A method as claimed in claim 5 whereinthe eatable having a bitter or metallic taste comprises at least onepharmaceutical having a bitter or metallic taste.
 12. A method asclaimed in claim 5 wherein the eatable having a bitter or metallic tasteis selected from the group consisting of the following compounds whichhave a bitter or metallic taste: amino acids, peptides, polypeptides andproteins.
 13. A method according to claim 5 wherein the tastand isincorporated in the eatable.